AU2002353691B2 - Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5) - Google Patents

Description

WO 03/042205 PCT/SE02/02055 1 PIPERIDINE DERIVATIVES AND THEIR USE AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY (ESPECIALLY The present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed in PCT/SE01/01053, EP- Al-1013276, WO00/08013, W099/38514 and W099/04794.

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a r6le in the maturation of cells of the immune system. Chemokines play an important rl1e in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8- 14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys or a) and Cys-Cys or 3) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins la and 1P (MIP-la and MIP-1).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several WO 03/042205 PCT/SE02/02055 2 chemokines, principally "regulated on activation normal T-cell expressed and secreted" (RANTES), rnacrophage inflammatory proteins (MIP) MIP-lac and MIP-1f and monocyte chemoattractant protein-2 (MCP-2).

This results in the recruitment of cells of the immune system to sites of disease. In many diseases it is the cells expressing CCR5 which contribute, directly or indirectly, to tissue damage. Consequently, inhibiting the recruitment of these cells is beneficial in a wide range of diseases.

is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection.

The present invention provides a compound of formula

R

0 0 2 N 4-JR5 (1)

R

wherein L is CH or N; M is CH or N; provided that L and M are not both CH; R' is hydrogen, C1- 6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1- 4 alkyl, CI-4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

14 alkyl)C(O)NH, S(0) 2

NH

2 C1- 4 alkylthio, S(O)(C 1 -4 alkyl) or S(0)2(C1-4 alkyl) or heteroaryl which itself optionally substituted by halo, C 14 alkyl, C 14 alkoxy, cyano, nitro, CF 3 (C1- 4 alkyl)C(O)NH, S(0) 2

NH

2

C

1 4 alkylthio, S(O)(C 14 alkyl) or S(0) 2 (C1- 4 alkyl)}], phenyl {optionally substituted by halo, C 1 4 alkyl, C 14 alkoxy, cyano, nitro, CF3, OCF 3 (C1- 4 alkyl)C(O)NH,

S(O)

2

NH

2

C

1 4 alkyithio, S(O)(C 1 -4 alkyl) or S(0) 2 (C1- 4 alkyl)}, heteroaryl {optionally substituted by halo, C1- 4 alkyl, C1.4 alkoxy, cyano, nitro, CF 3

(C

1 4 alkyl)C(O)NH, S(0) 2

NH

2

C

14 alkylthio, S(O)(C 1 -4 alkyl) or S(0) 2 (C1- 4 alkyl)}, S(0) 2 R, S(0) 2

NR

1

C(O)R

7 C(0) 2

(C

1 -6 alkyl) (such as tert-butoxycarbonyl), C(O) 2 (phenyl(CI.-2 alkyl)) (such as benzyloxycarbonyl) or C(O)NHR; and when M is CH R' can also be NHS(0) 2

R,

NHS(0) 2 NHR, NHC(O)R 7 or NHC(O)NHR 7

R

2 is phenyl or heteroaryl, either of which is optionally substituted by halo, C 1 4 alkyl, C 14 alkoxy, S(O)n(C 1 4 alkyl), nitro, cyano or CF 3 WO 03/042205 WO 031422Q5PCTSEO2O2O55 3

R

3 is hydrogen or C 1 4 alkyl;

R

4 is hydrogen, methyl, ethyl, allyl or cyclopropyl;

R

5 -is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C 1 2 )alkyl, heferoaryl(C 1 2 )alkyl,.

phenyl(C 1 2 alkyl)NH or heteroaryl(CI- 2 alkyl)NH; wherein the phenyl and heteroaryl rings of

R

5 are optionally substituted by halo, cyano, nitro, hydroxy, CI.

4 alkyl, C 1 4 alkoxy, S(O)k(CI- 4 alkyl), S(0) 2

NR'R

9

NHS(O)

2

(C

1 4 alkyl), NH 2

NH(CI-

4 alkyl), N(C 1 .4 alkyl) 2

NHC(O)NH

2

C(O)NH

2 C(O)NH(Cl.

4 alkyl), NHC(O(C 1 4 alkyl), CO 2 H, C0 2

(C

1 4 alkyl), C(O)(C 1 4 alkyl),

CF

3

CHF

2

CH

2 F, CH 2

CF

3 or OCF 3 k, m and n are, independently, 0, 1 or 2; R 6 is CI- alkyl. [optionally substituted by halo (such as fluoro), C 1 4 alkoxy, phenyl [which itself optionally substituted by halo, C 1 4 'alkyl, C 1 4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

1 4 alkyl)C(O)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2 (Cl.

4 alkyl)l or heteroaryl which itself optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3

(C

1 4 alkyl)C(O)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2

(CI-

4 alkyl)}II, C 3 7 cycloalkyl, pyranyl, phenyl optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

1 4 alkyl)C(O)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2

(C

1 4 alkyl) I or heteroaryl I optionally substituted by halo, C1- 4 alkyl, CI.

4 alkoxy, cyano, nitro,

CF

3

(C

1 4 alkyl)C(Q)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2

(C

1 4 alkyl)); R 7 is hydrogen, C 1 6 alkyl [optionally'substituted by halo (such as fluoro), C 1 4 alkoxy, phenyl which itself optionally substituted by halo, C 1 4 alkyl, CI.

4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

1 4 alkyl)C(O)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2 (Cl.

4 alkyl) I or heteroaryl I which itself optionally substituted by halo, CI- 4 alkyl, C 1 4 alkoxy, cyano, nitro,

CE

3

(C

1 4 alkyl)C(O)N}I, S(O) 2

NJ

2

C

1 4 alkylthio, S(O)(C1.

4 alkyl) Or S(O)2(C1A4 alkyl)}],

C

3 7 cycloalkyl, pyranyl, phenyl I optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

1 4 alkyl)C(O)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2

(C

1 4 alkyl) I or heteroaryl optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro,

CE

3

(C

1 4 alkyl)C(O)NH, S(O) 2

NH

2

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2

(C

1 4 alkyl)); R8 and R9 are, independently, hydrogen or C 1 4 alkyl, or together with a nitrogen or oxygen atom, may join to forn- a 5- or 6-membered ring which is optionally substituted with C 1 4 'alkyl, C(O)H or C(O)(C 1 4 alkyl); R1 and R" are, independently, hydrogen Or C 1 4 alkyl, or may join to form a 5- or 6membered ring which is optionally substituted with C 1 4 alkyl. or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl, C 1 4 alkoxy, S(O)mCI- 4 WO 03/042205 PCT/SEO2/02055 4 alkyl, S(O) 2

NH

2 S(0) 2

NH(CI-

4 alkyl), S(0) 2 N(C1- 4 alkyl) 2 NHS(0) 2

(C

1 4 alkyl), NH 2

NH(C

14 alkyl), N(C 1 -4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(C

1 4 alkyl), NHC(O)(C 1 -4 alkyl), CO 2 H, CO2(C1-4 alkyl), C(O)(C1- 4 alkyl), CF 3

CHF

2

CH

2 F, CH 2

CF

3 or OCF 3 or a pharmaceutically acceptable salt thereof or.a solvate thereof; provided that when R' is hydrogen or unsubstituted alkyl, R 4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of R 5 is substituted by one of: S(O)kCI-4 alkyl, NHC(O)NH 2

C(O)(C

1 4 alkyl), CHF 2

CH

2 F, CH 2

CF

3 or OCF 3 and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, Cl4 alkyl, C 1 4 alkoxy, S(O)kCI-4 alkyl, S(0) 2

NRR

9 NHS(0) 2 (C1- 4 alkyl), NH 2 NH(Cj.

4 alkyl), N(C1- 4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(C

1 4 alkyl), NHC(O)(C 1 4 alkyl), CO 2 H, CO 2 (C1-4 alkyl), C(O)(CI-4 alkyl),

CF

3

CHF

2

CH

2 F, CH 2

CF

3 or OCF3.

Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or ptoluenesulphonate.

The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.

Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl. Methyl is sometimes abbreviated to Me hereinbelow.

Fluoroalkyl includes, for example, one to six, such as one to three, fluorine atoms, and comprises, for example, a CF 3 group. Fluoroalkyl is, for example, CF 3 or CII 2

CF

3 Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.

Phenyl(C 1 2 alkyl)alkyl is, for example, benzyl, 1-(phenyl)eth-1-yl or 1-(phenyl)eth-2yl.

Heteroaryl(C 1 2 alkyl)alkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 1- (pyridinyl)eth-2-yl.

Phenyl(C1.

2 alkyl)NH is, for example, benzylamino. Heteroaryl(C1-2 alkyl)NH is, for example, pyridinylCH 2 NH, pyrimidinylCH 2 NH or pyridinylCH(CH 3

)NH.

Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, WO 03/042205 PCT/SE02/02055 oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazoly], oxazolyl, isoxazolyl, itnidazolyl, [1,2,41-triazolyl, pyridinyl, pyrimlidinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or 'benzthiophenyl), indazolyl, benzirnidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3benzothiadiazolyl, an imidazopyridinyl (such as imidazo[ 1,2a]pyridinyl), thieno[3 ,2blpyridin-6-yl, 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3beozothiadiazolyl, benzofurazan (also known as 2,1 ,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyridine (for example 1H-pyrazolojj3,4-b]pyridinyl), quinolinyl, isoquinolinyl, a naphthyridinyl (for example 1,6]naphthyridinyl or 1,8]naphthyridinyl), a benzothiaziny] or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or dioxide thereof. Heteroaryl can also be pyrazinyl. Heteroaryl is, for example, pyridinyl, pyrimidiniyl, indolyl or benzimidazolyl.

In one particular aspect the present invention provides a compound of formula (1) wherein L is CH or N; M is CH or N; provided that L and M are not both CH; R1 is hydrogen,

C

1 6 alkyl [optionally substituted by phenyl (which itself optionally substituted by. halo, C 1 4 alkyl, CI- 4 alkoxy, cyano, nitro, CF 3 CI- alkylthio,. S(O)(C 1 4 alkyl) or S(O) 2

(C

1 4 alkyl) I or heteroaryl (which itself optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro,

CE

3

C

1 4 alkylthio, S(O)(CI 4 alkyl) or S(O) 2 4 alkyl)}11, phenyl (optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3

C

1 4 alkylthio, S(O)(C 1 -4 alkyl) or S(O) 2

(C

1 4 alkyl) heteroaryl I(optionally substituted by halo, C 1 4 alkyl, C 1- alkoxy, cyano, nitro, CF 3

CI-

4 alkYlthio, S (O)(CI-4 alkyl) or S(O) 2 (Cl 1 4 alkyl)}1, S(O) 2 R' S(O) 2

NHR

7 C(O)R 7 I6

C(O)

2

(CI-

6 alkyl) or C(O)NHR and when M is CH R1 can also be NHS(O) 2 R

NHS(O)

2 N11R 7

NHC(O)R

7 or NHC(O)NHR 7

R

2 is phenyl or heteroaryl, either of which is optionally substituted in the ortho or meta position by halo, CI-4 alkyl, C 1 4 alkoxy, S(O)n(CI- 4 alkyl), nitro, cyano or CF 3

R

3 is hydrogen or C 1 4 alkyl; R 4 is hydrogen, methyl, ethyl, allyl or cyclopropyl; R 5 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(CI-2)alkyl, heteroaryl(C 1 2 )alkyl, phenyl(CI- 2 alkyl)NH or hetffroaryl(C 1 2 alkyl)NH; wherein the phenyl and heteroaryl rings of R 5 are optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl,

C

1 4 alkoxy, S(O)kCI-4 alkyl, S(O) 2

NR

8

NIIS(O)

2

(C

1 4 alkyl), NH1 2

NH(C

14 alkyl), N(C 14 alkyl) 2

NHC(O)NH

2

C(O)NH

2 C(O)NH(Cl.

4 alkyl), NHC(O)(CI- 4 alkyl), CO 2 H, C0 2

(CI-

4 alkyl), C(O)(CI- 4 alkyl), CF 3

CHF

2

CH

2 F, CH 2

CF

3 or OCF 3 R 8 and R 9 are, independently, hydrogen or C 1 4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6- WO 03/042205 PCT/SE02/02055 6 membered ring which is optionally substituted with 03.4 alkyl, C(0)H or OO)(04 alkyl); k and n are, independently, 0, 1 or 2; R 6 is C 1 6 alkyl [optionally substituted by phenyl I{which itself optionally substituted by halo, 01.4 alkyl, C 1 4 alkoxy, cyano, nitro, OF 3

C

1 4 alkylthio, S(0)(C.

4 alkyl) or S(0) 2

(CI-

4 alkyl)} or heteroaryl which itself optionally substituted by halo, C 1 4 alkyl, CI.

4 alkoxy, cyano, nitro, CF 3

C

1 4 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2

(CI-

4 alkyl) 03-7 cycloalkyl, phenyl t optionally substituted by halo, CI.

4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3 01.4 alkylthio, S (0)(C 1 4 alkyl) or S(0) 2

C

1 4 alkyl)}I or heteroaryl I{optionally substituted by halo, CI.

4 alkyl, C 1 4 alkoxy, cyano, nitro, OF 3 C1_ 4 alkylthio, S(O)(CI- 4 alkyl) Of S(0) 2 (Cl.

4 alkyl) R 7 is hydrogen, C 1 6 alkyl [optionally substituted by phenyl which itself optionally substituted by halo, 03.4 alkyl, C 1 4 alkoxy, cyano, nitro, CE 3 01.4 alkylthio,

S(O)(C

1 4 alkyl) or S(O) 2

(CI-

4 alkyl)}I or heteroaryl (which itself optionally substituted by halo, 01.4 alkyl, C 1 4 alkoxy, cyano, nitro, CE 3 01.4 alkylthio, S(O)(0 1 4 alkyl) or S(0) 2 (0 1 4 alkyl)j, C3.7 cycloalkyl, phenyl {optionally substituted by halo, C 1 4 alkyl, C1.4 alkoxy, cyano, nitro, OF 3 03.4 alkylthio, S(O)(CI- 4 alkyl) or S(O) 2

(CI-

4 alkyl) I or beteroaryl {optibinally substituted by halo, 01.4 alkyl, CI.

4 alkoxy, cyano, nitro, CE 3 01.4 alkylthio, S(O)(C 1 4 alkyl) or S(0) 2 (Cl.

4 alkyl) or a pharmaceutically acceptable salt thereof or a solvate thereof; provided that when R' is hydrogen or unsubstituted alkyl, R 4 is hydrogen' methyl or ethyl, L is OH and M is N, then the phenyl. or heteroaryl part of R 5 is substituted by one Of: S(0)kC].4 alkyl, NHCO)NH 2 C(0)(0 1 4 alkyl), CHF 2

CH

2 F, CH 2

CF

3 or 00F 3 and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C 1 4 alkyl, 01.4 aikoxy, S(O)kC1.4 alkyl, S(0) 2

NR

8

R

9 NHS(0) 2 (0 1 4 alkyl), NH 2

NH(C..

4 alkyl), N(OI..

4 alkyl)j 2 NHC(0)NH 2

CO)NH

2 O(0)NH(C1A4 alkyl), NHCO)(Cl.

4 alkyl), 00 2 H, 002(01.4 alkyl), O)03.4 alkyl),

CE

3 011F 2

OH

2 F, OH 2

CF

3 gr 00F 3 In another aspect the present invention provides a compound of the invention wherein when L and M are both N, and R1 is hydrogen, 01.-4 alkyl or phenyl (the phenyl being substituted with 0, 1 or 2 substituents selected from the list consisting of: fluoro, chioro, 03.4 alkyl, 03.4 alkoxy, cyano, OF 3 00F 3 (01.4 alkyl)C(0)NH and S(O) 2

NH

2 then the phenyl or heteroaryl moiety of R 5 carries a S(O) 2 (0 1 4 alkyl) substituent, and, optionally, one or more further substituents.

In a further aspect of the invention heteroaryl is pyrrolyl, thienyl, imidazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or quinolinyl.

In another aspect M is N and L is CH or N.

In yet another aspect L and M are both N.

WO 03/042205 PCT/SE02/02055 7 In a further aspect L is CH and M is N.

In a still further aspect L is N and M is CH.

In another aspect of the invention R' is hydrogen, C.-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], S(O) 2

S(O)

2

NHR

7 C(0)R 7 C(0) 2 (C1- 6 alkyl) or C(O)NHR7; and when M is CH R' can also be NHS(0) 2

R

6 NHS(0) 2

NHR

7

NHC(O)R

7 or NHC(O)NHR 7

R

6 is C1- 6 alkyl [optionally substituted by phenyl (which itself optionally substituted by halo}], C 3 7 cycloalkyl, phenyl {optionally substituted by halo}; and R 7 is hydrogen, C 1 6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C 3 7 cycloalkyl, phenyl {optionally substituted by halo}.

In another aspect of the invention R' is C1-6 alkyl [substituted by phenyl {which itself optionally substituted by halo}], S(0) 2

R

6

S(O)

2

NHR

7

C(O)R

7 C(0) 2

(C

1 -6 alkyl) or

C(O)NHR

7 and when M is CH R 1 can also be NHS(0) 2

R

6 NHS(0) 2

NHR

7

NHC(O)R

7 or

NHC(O)NHR

7

R

6 is C-6 alkyl [optionally substituted by phenyl (which itself optionally substituted by halo C 3 7 cycloalkyl, phenyl {optionally substituted by halo}; and R 7 is hydrogen, C1.6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo} C3-7 cycloalkyl, phenyl optionally substituted by halo In a further aspect of the invention R' is S(0) 2

R

6

C(O)R

7 C(0)z(C.- 6 alkyl) or

C(O)NHR

7 and when M is CH R' can also be NHS(0) 2

R

6 or NHC(O)R 7 and R 6 and R 7 are as defined above.

In another aspect of the invention R' is hydrogen, C1-6 alkyl [optionally substituted by phenyl (which itself optionally substituted by halo)], S(O) 2

R

6

C(O)R

7 C(0)2(C1.6 alkyl) or

C(O)NHR

7 and when M is CH R 1 can also be NHS(0) 2

R

6 or NHC(O)R7; R 6 is C 1 6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo)], C3-7 cycloalkyl, phenyl {optionally substituted by halo); and R 7 is hydrogen, C 16 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}.

In a further aspect R 1 is phenyl (optionally substituted by halo (for example fluoro), C1-4 alkyl (for example methyl), C 1 4 alkoxy (for example methoxy), CF 3 or OCF 3 S(0) 2 (C-4 alkyl) (for example S(0) 2

CH

3 S(0) 2

CH

2

CH

3 or S(0) 2

CH(CH

3 2

S(O)

2

(C

14 fluoroalkyl) (for example S(0) 2

CF

3 or S(0) 2

CH

2

CF

3 S(0) 2 phenyl (optionally substituted (such as monosubstituted) by halo (for example chloro), cyano, C1-4 alkyl, C1- 4 alkoxy, CF 3

OCF

3 S(0) 2

(C

1 4 alkyl) (for example S(0) 2

CH

3 or S(0) 2

CH

2

CH

2

CH

3 or S(0) 2

(CI.

4 fluoroalkyl) (for example S(0) 2

CH

2

CF

3 benzyl (optionally substituted by halo (for example chloro or fluoro), C1.4 WO 03/042205 PCT/SEO2/02055 8 alkyl, C 14 alkoxy (for example methoxy), CF 3 or OCF 3 benzoyl (optionally substituted by halo (for example chloro or fluoro), C1- 4 alkyl (for example methyl), C 1 4 alkoxy, CF 3 or

OCF

3 C(O)NHphenyl (optionally substituted by halo (for example fluoro), C1- 4 alkyl, C 1 -4 alkoxy, CF 3 or OCF 3

S(O)

2 thiophenyl, CH 2 pyridinyl, CH 2 quinolinyl or CH 2 thiazolyl.

In yet another aspect R' is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoro), C 1 4 alkyl (for example methyl) or C-4 alkoxy (for example methoxy)), S(0) 2

(C

14 alkyl) (for example S(0) 2

CH

3 S(0) 2

CH

2

CH

3 or S(0) 2

CH(CH

3 2 S(0) 2 (C1- 4 fluoroalkyl) (for example S(0) 2

CF

3 or S(0) 2

CH

2

CF

3

S(O)

2 phenyl (optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, CF 3

OCF

3 S(0) 2

(C

14 alkyl) (for example S(0) 2

CH

3 or S(0) 2

CH

2

CH

2

CH

3 or S(0) 2 (C1- 4 fluoroalkyl) (for example S(0) 2

CH

2

CF

3 benzyl (optionally substituted by halo (for example chloro or fluoro) or C 1 4 alkoxy (for example methoxy)), benzoyl (optionally substituted by halo (for example chloro or fluoro) or C1- 4 alkyl (for example methyl)), C(O)NHphenyl (optionally substituted by halo (for example fluoro)), S(O) 2 thiophenyl, CH2pyridinyl, CH 2 quinolinyl or CH 2 thiazolyl.

In a further aspect R' is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoro) or C 1 4 alkyl (for example methyl)), S(0) 2

(CI-

4 alkyl) (for example S(0) 2

CH

3 S(0) 2

CH

2

CH

3 or S(0) 2

CH(CH

3 2 S(0) 2 (C1- 4 fluoroalkyl) (for example S(0) 2

CF

3 or S(0) 2

CH

2

CF

3 S(0) 2 phenyl (optionally substituted (such as mono-substituted) by CF 3

OCF

3 or S(0) 2 (C1- 4 alkyl) (for example S(0) 2

CH

3 benzyl (optionally substituted by halo (for example chloro or fluoro) or C 1 4 alkoxy (for example methoxy)), benzoyl (optionally substituted by halo (for example chloro or fluoro)), C(O)NHphenyl (optionally substituted by halo (for example fluoro)), CH 2 pyridinyl, CH 2 quinolinyl or CH 2 thiazolyl.

In a still further aspect R' is hydrogen, C1-6 alkyl [optionally substituted by phenyl which itself optionally substituted by halo, C1- 4 alkyl, C1- 4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

1 4 alkyl)C(O)NH, S(0) 2

NH

2 or S(0) 2 (C1- 4 alkyl) or heteroaryl which itself optionally substituted by halo, C 14 alkyl or (C1- 4 alkyl)C(O)NH}], phenyl {optionally substituted by halo, C1- 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3

OCF

3 (C1-.

4 alkyl)C(O)NH, S(0) 2

NH

2 or S(0) 2 (C1- 4 alkyl) heteroaryl (optionally substituted by halo, C1- 4 alkyl or (C 1 -4 alkyl)C(O)NH), S(0) 2

R

6

S(O)

2 NR'OR", C(O)R 7 or C(O)NHR 7 and when M is CH R' can also be NHC(O)R 7

R

6 is Ci- 6 alkyl [optionally substituted by halo (such as fluoro), phenyl {which itself optionally substituted by halo, C 14 alkyl, C1- 4 alkoxy, cyano, nitro, CF 3

OCF

3

(C

1 4 alkyl)C(O)NH, S(0) 2

NH

2 or S(0) 2

(C

14 alkyl)) or heteroaryl which itself optionally substituted by halo, C 1 4 alkyl or (C 1 4 alkyl)C(O)NH}], phenyl [optionally substituted by WO 03/042205 PCT/SE02/02055 9 halo,.C 1

I

4 alkyl, C 1 4 alkoxy, cyano, nitro, CF3, OCF 3 (C1- 4 alkyl)C(O)NH, S(0) 2

NH

2 or S(0) 2 (C1- 4 alkyl)} or heteroaryl {optionally substituted by halo, C1- 4 alkyl or (C1-4 alkyl)C(O)NH} ;R 7 is hydrogen, C 1 -6 alkyl [optionally substituted by halo (such as fluoro), C1.

4 alkoxy, phenyl {which itself optionally substituted by halo, C14 alkyl, C 1 4 alkoxy, cyano, nitro, CF3, OCF 3

(C

1 4 alkyl)C(O)NH, S(0) 2

NH

2 or S(0) 2

(C

14 alkyl)} or heteroaryl {which itself optionally substituted by halo, C 1 4 alkyl or (C1- 4 alkyl)C(O)NH}], C 3 -7 cycloalkyl, pyranyl, phenyl {optionally substituted by halo, C 14 alkyl, C1- 4 alkoxy, cyano, nitro, CF 3

OCF

3 (C1- 4 alkyl)C(O)NH, S(0) 2

NH

2 or S(0) 2 (C1- 4 alkyl)} or heteroaryl {optionally substituted by halo, C1- 4 alkyl or (C 1 4 alkyl)C(O)NH}; and, R 10 and R" 1 are, independently, hydrogen or C 14 alkyl.

In a further aspect R 1 is phenyl (optionally substituted (such as mono-substituted) by.

halo (for example fluoro) or C 14 alkyl (for example methyl)), S(0) 2

(CI-

4 alkyl) (for example S(0) 2

CH

3 or S(0) 2

CH

2

CH

3 S(0) 2 (C1- 4 fluoroalkyl) (for example S(0) 2

CF

3 S(0) 2 phenyl (optionally substituted (such as mono-substituted) by CF 3 or OCF 3 benzyl, benzoyl (optionally substituted by halo (for example chloro or fluoro)) or C(O)NHphenyl (optionally substituted by halo (for example fluoro)).

In yet another aspect of the invention R 2 is phenyl or heteroaryl, either of which is optionally substituted in the ortho or meta position by halo, C 1 4 alkyl, C 1 4 alkoxy, S(O)n(C 1 4 alkyl), nitro, cyano or CF 3 wherein n is 0, 1 or 2, for example 0 or 2. (Ortho and meta positions are ortho and meta relative to the position of attachment of that ring to the structure of formula In a still further aspect R 2 is optionally substituted phenyl (such as optionally substituted by halo (such as chloro or fluoro), cyano, methyl, ethyl, methoxy, ethoxy or CF 3 In one aspect the substitution is on the ortho or meta position of the phenyl ring.

In another aspect R 2 is optionally substituted phenyl (such as optionally substituted by halo or CF 3 For example R 2 is 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF 3 phenyl. In a further aspect R 2 is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 3,4difluorophenyl or 3,5-difluorophenyl. In another aspect R 2 is phenyl, 3-fluorophenyl, 4fluorophenyl, 3,4-difluorophenyl or 3,5-difluorophenyl. In a still further aspect of the invention R 2 is phenyl or 3-fluorophenyl.

In another aspect of the invention R 3 is hydrogen or methyl. In a further aspect of the invention when R 3 is C 14 alkyl (such as methyl) the carbon to which R 3 is attached has the R absolute configuration. In yet another aspect of the invention R 3 is hydrogen.

WO 03/042205 WO 03/42205PCT/SE02/02155 In a further aspect of the invention R 4 is ethyl.

In a still further aspect the present invention provides a compound of the invention wherein R 5 is phenyl(C 1 2 )alkyl, phenyl(C 1 2 alkyl)NH, phenyl, heteroaryl or heteroaryl(C 1 2 )alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, CI-4 alkyl, C 1 4 alkoxy, S(O)kCI- 4 alkyl, S(O),NR 8

NHS(O)

2

(C

1 4 alkyl),

NH

2

NH(C

1 4 alkyl), N(C 1 4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(C

1 4 alkyl),

NHC(O)(C

1 4 alkyl), CO 2 H, C0 2

(C

1 4 alkyl), C(O)(C1p4 alkyl), CF 3

CHF

2 CHzF, CH 2

CF

3 Or

OCF

3 and R8 and R9 are, independently, hydrogen or C 1 4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with

C

1 4 alkyl, C(O)H or C(O)(C 4 alkyl); and k is 0, 1 or 2 (for example, 2).

In another aspect the invention provides a compound of the invention where in R 5 is phenyl(C 1 2 )alkyl or phenyl(Cl- 2 allcyl)NH; wherein the phenyl rings of R 5 are optionally substituted by halo, cyano, nitro, hydroxy, CI- 4 alkyl, CI-4 alkoxy, S(O)kCl- 4 alkyl,

S(O),NR

8

NHS(O)

2

(CI-

4 alkyl), NH 2

NH(C

1 4 alkyl), N(C 1 4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(C

1 4 alkyl), NHC(O)(C 1 4 alkyl), C0 2 H, C0 2

(C

1 4 alkyl), C(O(C 1 4 alkyl),

CE

3

CHF

2

CH

2 F, CH 2

CF

3 or OCF 3

R

8 and R 9 are, independently, hydrogen or CI- 4 alkyl, or together with a nitrogen or oxygen atom, may join to form a or, 6-membered ring which' is optionally substituted with C 1 4 alkyl, C(O)H or C(O)(CI.

4 alkyl); and k is 0, 1 or 2.

In a still further aspect of the invention R 5 is phenyl, heteroaryl, phenyl(Cl- 2 )alkyl or heteroaryl(C 1 2 )alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl, C 1 4 alkoxy, S(O)kCI-4 alkyl, S(O) 2 NR R

NHS(O)

2 (Cl 1 4 alkyl), NH 2

NH(C..

4 alkyl), N(CI- 4 alkYl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(C

1 4 alkyl), NHC(O)(C 1 4 alkyl), CO 2 H, C0 2

(C

1 4 alkyl), C(O)(CIA4 alkyl), CE 3

CI-IF

2

CH

2 F7, CH 2

CF

3 or QCF 3 k is 0, 1 or 2; and R 8 and R 9 are, independently, hydrogen or

C

1 4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C 1 4 alkyl, C(O)H or C(O)(Cp4 alkyl).

In another aspect R 5 is phenyl or beuzyl; wherein the aromatic rings are optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl, C 1 4 alkoxy, S(O)kCl.4 alkyl,

S(O),NR

8

NHS(O)

2 (Cl.

4 alkyl), NH 2

NH(CI.

4 alkyl), N(Cl-4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(CI-

4 alkyl), NHC(O)(Cl.

4 alkyl), C0 2 H1, C0 2 (Cl.

4 alkyl), C(O)(C 1 4 alkyl),

CE

3 ClIP 2

CH

2 F, CH 2

CF

3 or OCF 3 k is 0, 1 or 2; and R 8and R 9 are, independently, hydrogen or C 1 4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6membered ring which is optionally substituted with CI.

4 alkyl, C(O)H or C(O)(CI- 4 alkyl), WO 03/042205 PCT/SE02/02055 In .a further aspect R 5 is phenyl or benzyl; wherein the aromatic rings are optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl, C 1 4 alkoxy, S(O)2C]p4 alkyl,

S(O)

2 NR 8

NHS(O)

2 (Cl 1 4 alkyl), NH 2

NH(C

14 alkyl), N(C 1 4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NH(CI-

4 alkyl), NHC(O)(CIA4 alkyl), CO 2 H, C0 2

(CI-

4 alkyl), C(O)(Cl.

4 alkyl),

CE

3 and R 8 and R 9 are, independently, hydrogen or C 1 4 alkyl.

In another aspect R 5 is NHCH 2 phenyl wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl, C 1 4 alkoxy, S(O) 2

C

1 4 alkyl, S(O) 2

NR

8

R

9

NHS(O)

2 (Cl 1 4 alkyl), NH 2

NH(C

1 4 alkyl), N(C 1 4 alkyl) 2

NHC(O)NH

2

C(O)NH

2 C(O)NH(Cl- 4 alkyl), NHC(O)(C 1 -4 alkyl), CO 2 H, C0 2

(C

1 4 alkyl), 4 alkyl), CF 3 and

R

8 and R 9 are, independently, hydrogen or CI-4 alkyl.

In yet another aspect R 5 is benzyl. wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, Ci..

4 'alkyl, C 1 4 alkoxy, S(O) 2

C

1 4 alkyl, S(O) 2 NRBR 9

NHS(O)

2 (Cl 1 4 alkyl), NH 2

NH(C

1 4 alkyl), N(C 1 4 alkyl) 2

NHC(O)NH

2

C(O)NH

2

C(O)NII(C

1 4 alkyl), NHC(O)(C 1 4 alkyl), CO 2 H, CO 2 (C1 4 alkyl), C(O)(Clp4 alkyl), CF and

R

8 and R 9 are, independently, hydrogen or C 1 4 alkyl.

In another aspect R 5 is NHCH 2 phenyl wherein the aromatic ring is optionally substituted by halo (such as fluoro, chioro or bromo), cyano, C]-4 alkyl (such as methyl), C 1 4 alkoxy (such as methoxy) or S (O) 2

C

4 alkyl (such as S(O) 2

CH

3 In yet another aspect R 5 is benzyl. wherein the aromatic ring is optionally substituted by halo (such as fluoro, chloro or bromo), cyano, C 1 4 alkyl. (such as methyl), CI- 4 alkoxy (such as methoxy) or S(O) 2 Cl.

4 alkyl (such as S(O) 2

CH

3 In a still further aspect R 5 is phenyl or beuzyl, wherein the aromatic ring is substituted (for example in the para-position) by S(O) 2

CI-

4 alkyl and the ring is optionally further substituted by halo, cyano, nitro, hydroxy, CI- 4 alkyl or CI.

4 alkoxy.

In another aspect R 5 is NHCH 2 phenyl or brnzyi, wherein the aromatic ring is substituted (for example in the para-position) by S(O) 2

C

1 4 alkyl (such as S(O) 2

CH

3 and the ring is optionally further substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl or CIA 4 alkoxy.

In another aspect R 5 is NHCH 2 phenyl wherein the aromatic ring is substituted (for example in the para-position) by S(O) 2

CI-

4 alkyl (such as S(O) 2 CHA) R 5 is, for example

NHCH

2 (4-S (O) 2

CH

3

-C

6

H

4 In another aspect R5 is benzyl, wherein the aromatic ring is substituted (for example in the para-position) by S(O) 2

CI-

4 alkyl (such as S(O) 2 CHA) R5 is, for example CH 2 (4- S (O) 2

CH

3

-C

6

H

4 WO 03/042205 PCT/SE02/02055 12 The carbon labelled A in. the representation of formula shown below, is always chiral.

0 14 R

R

When L is N the carbon labelled A has, for example, the S absolute configuration. When L is CH the carbon labelled A has, for example, the R absolute configuration.

In another aspect the present invention provides a compound of formula (Ia):

R

S ,S(OLMe wherein L, M and R 1 are as defined above.

In a further aspect the present invention provides a compound of formula (Ib):

R\

M--.;0NA Kid} M wherein L, M and R 1 are as defined above; and R is hydrogen, one or two fluorine atoms, S(O)n(CI.4 alkyl) or C 1 4 alkoxy; and n is 0, 1 or 2 (for example, 2).

In another aspect the present invention provides a compound of formula (Ic): WO 03/042205 PCT/SE02/02055 0 )),Me wherein L, M and R 1 are as defined above; and R is hydrogen, one or two fluorine atoms,

S(O),(C

1 4 alkyl) or Ci- 4 alkoxy; and n is 0, 1 or 2 (for example, 2).

In a still further aspect the present invention provides a compound of formula (Id): 1\ n

//R

wherein L, M and R 1 are as defined above; R is hydrogen, one or two fluorine atoms, alkyl) or C 1 4 alkoxy; X is NHCH 2 NH or CH 2 n is 0, 1 or 2 (for example, and R* is halo (such as fluoro, chloro or bromo), cyano, C1-4 alkyl (such as methyl), C1- 4 alkoxy (such as methoxy) or S(0) 2 C1- 4 alkyl (such as S(0) 2

CH

3 In another aspect the present invention provides a compound of formula (Ie):

R

M

0 0 L N 0 (le) wherein L, M and R 1 are as defined above.

In yet another aspect the present invention provides a compound of formula (If): WO 03/042205 PCT/SE02/02055 14

R

N N (If) 0

S=O

0 wherein L, M, X and R 1 are as defined above.

In a still further aspect the present invention provides a compound of formula (Ig): Qo NN (ig) k 0 wherein R 5 is as defined above.

The compounds listed in Tables I to VI illustrate the invention.

TABLE I Table I comprises compounds of formula (Tb).

RM

Compound L M R R I LCMS No. (MIT-i) 1 N N H Formyl 555 2 N N H iso-butyryl -597 3 N N H Acetyl 569 4 N N H Bcnzoyl 631 N N H Ethyl 555 6 N N H Methyl 541 7 N N H Benzeiiesulfonyl 667 8 N CH H Benzyl 616 9 N CH H Acetyl 568 N CH H Benzylaminocarbonyl 659 I11 N CHI H Ethoxycarbonyl 598 12 N CHI H Methyl 540 13 N CH H Phenylacetylaniino 659 14 N CH H- Acetylamino 583 N CH H Methanesulfonylamino 618 16 N CHI H Benzenesulfonylamino 681 17 CH N H H 526 18 CH N H Benzyl 616 19 CII N H Phenylacetyl 644 CH N H iso-butyryl 596 21 CH N H Acetyl 568 22 CHI N H Cyclohexylamainocarbonyl 651 23 CII N H tert-butyloxycarbonyl 626 24 CII N H 4-Chlorobenzoyl 664 CII N H Ethyl 554 26 CHI N H Methyl 540 27 CII N H Ethanesulfonyl 618 28 CH N H Methanesulfonyl, 604 29 N CH H Phenylureido 660 N CHI H j-Propylaninocarbonyl 611 31 N CH H 4-Chiorophenylarninocarbonyl 679 32 N CH H 4-Fluorophenylamninocarbonyl 663 33 N CHI H 4-Chlorobenzoylamino 679 34 N N H Phenylaminocarbonyl 546 N N H Propylaniinocarbonyl 612 36 N N H Methanesulfonyl 605 37 N N H Ethanesulfonyl 619 38 N N H 1-Methylethanesulfonyl 633 39 N N H Phenylmethanesulfonyl N N H Beuzenbsulfonyl (S-isomer) 41 CH N H Benzoyl 42 CH N H Benzenesulfonyl 43 CH N H iso-propyisulfonyl 44 CH N H Phenylaminocarbonyl N N H phenyl 603 46 N N H 4-fluorophenyl 621 47 N N H 4-methoxyphenyl 633 48 N N H 2-chlorophenyl 637 49 N N H 4-chiorophenyl 637 N N H 3-chiorophenyl 637 51 N N H 2-fluorophenyl 637 52 N N H 4-methanesulphonylbenzoyl 709 53 N N H 2-methanesulphonylbenzensulphonyl 745 54 N N H 3-methanesulphonylbenzoyl 709 N N H 3-fluorophenyl 621 56 N N 3-fluoro phenyl 621 57 N N 3-fluoro 4-iiethiaiesuphonylphenyl 699 58 N N 3-fluoro benzenesulphonyl 685 59 N N 3-fluoro 4-methanesulplionylbenzenesulphonyl 763 N N 3-fluoro ethanesuiphonyl 637 61 N N 3-fluoro methanesuiphonyl 623 62 N N 3-fluoro 4-chlorophenyl 655 63 N N 3-fluoro 3-chiorophenyl 655 64 N N 3-fluoro 2-fluorophenyl 639 N N 3-fluoro 4-fluorophenyl 639 66 N N H 5-Bromopyrimidin-2-yl 683 67 N N 3-fluoro 3-fluorophenyl 639 68 CH N 3-fluoro pyridin-3-ylmethyl 635 69 CH N 3-fluoro pyridin-4-ylmethyl 635 CH N 3-fluoro quinolin-2-ylmethyl 685 71 CH N H pyridin-2-ylmethyl 617 72 CH N H pyridin-3-ylmethyl 617 73 CH N H pyridin-4-ylmethyl61 74 CH N H quinolin-2-ylmethyl 667 CH N H quinolin-4-ylmethyl 667 76 CH N H 2-imidazolylmethyl 605 77 CH N H (1-methiyl-2-imiidazolyl)methyI 620 78 CH N H 2-pyrrolylmethyl 605 79 CH N H (1-methyl-2-pyrrolyl)methyl 619 CH N H 2-thiazolylmethyl 623 81 CH N H 4-chiorophenylmethyl 650 82 CH N H 3-chiorophenylmethyl 650 83 CH N H 2-chiorophenylmethyl 650.

84 CH N 1-1 4-fluorophenylmethyl 634 CH N H 4-methoxyphenylnethyl 646 86 CH N H Hydrogen 526 87 CH N H Hydrogen 543 88 CH N H methyl 540 89 CH N H acetyl 568 CH N H cyclohexylarniinocarbonyl 651 91 CHI N 3-fluoro methanesuiphonyl 622 92 CH N 3-fluoro ethanesulphonyl 635 93 CHI N 3-fluoro isopropylsuiphonyl 650 94 CHI N 3-fluoro bcnzcnesulphonyl 684 CH N 3-fluoro 4-methanesulphonylbenzenesulphonyl 762 96 CHI N 3-fluoro 4-chlorobenzpyl 682 97 CH N 3-fluoro 4-methoxyphienylmethylaminocarbonyl 707 98 CHI N 3-fluoro cyclohexylarminocarbonyl 668 99 CH N 3-fluoro phenylamiinocarbonyl 663 100 CH N 3-fluoro phenylmethylamrinocarbonyl 677 101 CHI N 3-fluoro (4-sulphonarnidophenyl)methylcarbonyI 741 1.02 -CH N 3-fluoro pyran-4-ylcaibonyl 656 103 CH N H 4-fluorobenzoyl 648 104 CHI N H 3-fluorobenzoyl 648 105 CH N H 2-fluorobenzgyl 648 106 CH N H 2-chlorobenzpyl 664 107 CII N H 3-chlorobenzpyl 664 108 CH N H 2-methylbenzoyl 644 109 CH N H 3-methylbenio 1 644 110 CH N H 4-methylbenzoyl 644 I11 CH N TH cyclopentylcarbonyl 622 112 CH N H propionyl 582 113 CH N H cyclopropylcarbonyl 594 114 CH N H pyrazin-2-ylcarbonyl 632 115 CH N H 3-methanesulphonylbenzoyl 708 116 CH N H (2-methylthiazol-4-yl)carbonyl 651 117 Cil N H methoxymethiylcarbonyl 598 118 CH N H 2,2,2-trifluoroethylcarbonyl 636 119 CH N H 3-cyanophenylaminocarbonyl 670 120 CH N H 3-fluorophenylaminocarbonyl 663 121 CH N H '3-chiorophenylaminocarbonyl 679 122 CH N H 3-methoxyphenylaminocarbonyl 675 123 CH N H 2-methyiphenylamninocarbonyl 659 124 CH N H pyran-4-yllcarbonyl 638 125 CH N H trifluoroacetyl 622 126 CH N H 4-chlorophenylaminocarbonyl 679 127 CH N H 4-fluorophenylaminocarbonyl 663 128 CH N H 4-methoxyphenylamrinocarbonyl 675 129 CH N H 2,5-difluorophenylaminocarbonyl 681 130 CH N H 3,4-dichiorophenylarninocarbonyl 713 131 CII N H 2-methoxyphenylarninocarbonyl 675 132 CH N H 2-chiorophenylamninocarbonyl 279 133 CHI N H trifluoramethaniesuiphonyl 658 134 N N H 4-methanesulphonylbenzenesulphonyl 745 135 N N H 4-cyanobenzenesulphonyl 692 136 N N H 2-trifluoromethoxybenzenesulphonyI 137 N N ]H .3-chlorobenzenesulphaonyl 701 138 N N H 4-trifluoromethylbenzenesulphonyl 735 139 N N H 4-trifluoromethoxybenzenesulphonyl 140 N N H 4-chlorobenzenesulphonyl 701 141 N N H (3,5-dimethylisoxazolyl)sulphonyl 686 142 N N H 2-thienylsuiphonyl 673 143 N N H (2-acetylamnino-3-methyl)thiazol-5-ylsulphonyI 745 144 N N H 4-acetylaminobenzenesulphonyl 724 145 CHI N 3-fluoro phenyl 620 146 CH N 3-fluoro 4-methoxyphenyl 650 147 CH N 3-fluoro 4-fluorophenyl 638 148 CH N H 3-chiorophenyl 654 149 CHI N H 4-chiorophenyl 654 150 N N H 2-chlorobenzenesulphonyl 701 151 N N H 4-chlorobenzoyl 665 152 CH N H tert-butoxycarbonyl 626 153 CH N 3-fluoro tert-butoxycarbonyl 612 154 CH N H 2,2,2-trifluoroethanesuiphonyl 672 155 N N 4-fluoro methanesulphonyl 623 156 N N 4-fluoro 4-methanesulphonylbenzenesulphonyl 763.3 157 N N 3,4-difluoro methianesuiphonyl 641.4 158 N N 3-chioro methanesuiphonyl 639 Table HI Table II comprises compounds of formula (1c).

M

'S(O)

2 Me 2 N N H S or R 4-methanesulphonylbenzenesulphonyl 745 3 N N H S or R 3-methylphenyl 617 4 N N H S orR 4-methylphenyl 617 N N H S or R 2-methylphenyl 617 6 N N H S or R 2-methoxyphenyl 633 7 N N H S or R 3-methoxyphenyl 633 8 N N H S or R 2,6-dimethyiphenyl 631 9 N N H S or R 2-cyanophenyl 628 N N H S or R 2-nitrophenyl 648 11 N N H S or R 2-methyithiophenyl 649 12 N N H S or R 4-fluorophenyl 621 13 N N H S or R 2,6-dichiorophenyl 672 14 N N H S or R n-propanesulphonyl 633 N N H S or R 2,2,2-trifluoroethanesulphonyl 673 16 N N 3-fluoro S or R 4-methanesulphonylbenzenesulphonyI 17 N N 3-fluoro R or S 4-methainesulphonylbenzenesulphonyl 18 CH N H R ethanesuiphonyl 654 19 CH N H S ethanesuiphonyl 654 CH N H R methanesuiphonyl 604 21 CH N H S methanesuiphonyl 604 22 CH N 3-fluoro R ethanesuiphonyl 636 23 CH N 3-fluoro s ethanesulphonyl 636 24 CH N H R benzyloxycarbonyl 659 CH N- H R phenylaminocarbonyl 26 CH N H R 4-chlorobenzoyl 27 CH N H R 4-methanesulphonylbenzenesulphonyI 28 CH N 3-fluoro R 4-chlorobenzoyl 29 CH N 3-fluoro S 4-chlorobenzoyl CH N 3-fluoro R 4-methanesulphonylbenzenesulphonyl 31 CH N 3-fluoro S 4-methanesulphonylbenzenesulphonyI 32 CH N 3,5-difluoro R trifluoromethanesuiphonyl 694 33 CH N H R 4-fluorobenzoyl 648 34 CH N H S 4-fluorobenzoyl 648 CH N H R hydrogen 526 36 CH N H R trifluoromethanesuiphonyl 658 37 CH N H S trifluoromethanesuiphonyl 658 38 CH N 2-methylthio, R methanesuiphonyl 650 39 CH N H R N,N-dimethylaminosulphonyl 633 Table MI Table ff1 comprises compounds of formula (Id).

Compound L M X R R* R' LCMS No.

(MH+)

1 N N NHCH 2 H 4-methanesuiphonyl benzenesulphonyl 682 2 N N NHCH 2 H 4-methanesuiphonyl benzoyl 646 3 N N NHCH 2 H 4-methanesuiphonyl ethanesuiphonyl 634 4 N N NHCH 2 H 4-methanesuiphonyl methanesuiphonyl 620 N N NHCH 2 H 4-methanesuiphonyl 4-chlorobenzoyl 680 6 CH N NHCH 2 H 4-methanesuiphonyl benzenesuiphonyl 681.

7 CH N NHCH 2 H 4-methanesuiphonyl ethanesulphony] 633 8 CH N NHCH 2 H 4-methanesuiphonyl hydrogen 541 9 CH N NHCH 2 H 4-methanesuiphonyl methanesuiphonyl 619 CH N NHCH 2 H 4-methanesuiphonyl 4-methanesulphonylbenzenesulphonyl 11I CH N NHTCH- 2 H4 4-methanesuiphonyl phenylmethylcarbonyl 659 12 CH N NHCH 2 H 4-methanesuiphonyl 4-chlorobenzoyl 679 13 CH N NHCH 2 H 4-methanesuiphonyl cyclohexylamninocarbony 666 14 GB N NHCH 2 H 4-methanesuiphonyl 4 -fluorophenylmethylaminocarbonyl 692 CH N NHCH 2 H 4-methanesuiphonyl 4-methanesulphonylbenzoyl 723 16 CH N NHCH 2 H 4-methanesuiphonyl pyridin-2-ylmethylcarbonyl 660 17 GB N NHCH 2 H 4-methanesuiphonyl pyridin-3-ylmethylcarbonyl 660 18 GB N NHCH 2 H hydrogen ethanesuiphonyl 555 19 CH N NHCH 2 H 4-methoxy etlianesuiphonyl 585 CB N NHCH 2 H 4-fluoro ethanesulphonyl 573 21 GB N NHCH 2 H 3-methyl ethanesulphonyl 569 22 CH N NI-IG 2 H 3-methoxy ethanesulphonyl 571 23 GB N NB H 3-chioro ethanesulphonyl 574 24 GB N NH H 2-methyl ethanesuiphonyl 554 GB N NH B 4-bromo ethanesuiphonyl 621 26 GB N NH H 3-cyano ethanesuiphonyl 566 27 GH N NHGH 2 H hydrogen benzenesulphonyl 603 28 GB- N NBGH 2 H 4-methoxy benizenesulphonyl 633 29 GB N NBCH 2 B 4-fluoro benzenesulphonyl 621 GH N NHCH 2 H 3-methyl benzeriesulphonyl 616 31 CH N NH H 3-fluoro benzenesulphonyl 607 32 CE N NH H 3-methoxy benzenesulphonyl 619 33 CH N NH H 3-chioro beuzenesuiphonyl 623 34I CH N NH H 2-methyl benzenesulphonyl 603 CH N NHl H 4-bromo benzenesulphonyl 669 36 CH N NH H- 3-cyano benzenesulphonyl 614 37 CH N CIT 2 3-fluoro 4-suiphonanido teit-butyloxycarbonyl 645 38 CH N CH 2 3-fluoro, 4-suiphonam-ido hydrogen 545- 39 CE N CE 2 3-fluoro 4-suiphonamido 4-methanesulphonylbenzenesulphonyl 763 CIT N CIT 2 3-fluoro, 4-suiphonamido cyclohexylaminocarbonyl 670 41 CE N CE 2 3-fluoro 4-suiphonamido methanesuiphonyl 623 42 CHI N CH 2 3-fluoro 4-suiphonamido ethanesuiphonyl 637 43 CH N NHCH 2 H 4-methanesuiphonyl 1-methylethanesuiphonyl 647 PCT/SE02!02055 WO 0310412205 29 Table IV Table IV comprises compounds of formula (le).

Compound. L M Stereochem RLCM

S

No.

(MH+)

1 N N S or R benzenesulphonyl 682 2 N N S or R ethanesuiphonyl 634 3 N N S or R rnethanesulphonyl 620 4 CH N Rmethanesulphonyl 650 Table V Table V comprises compounds of formula (If).

Rk

M

L

No N (If

I,S~

0 Compound L M X

LCMS

No.

(MIJ+)

1 N N CH 2 benzenesulphonyl 681 2 3 N N

N

NHCH

2

NHCH

2 benzenesulphonyl methanesuiphoflyl 634 WO 03/042205 PCT/SE02/02055 Table VI Table VI comprises compounds of formula (Ig).

N ig) o=s

NR

0 Compound No R- LCMS

(MH

1 pyridin-2-ylCH 2 589 2 pyridin-3-ylCH 2 589 3 pyridin-4-ylCH 2 589 In yet another aspect the invention provides each individual compound listed in the tables above.

The compounds of formula (If) and (Ig) can be prepared as shown below (for example in Schemes 2 and 3, with Scheme 1 showing the preparation of an intermediate.) In Schemes 1 to 3: PG is a protecting Group; Ac is acetyl; Boc is tertbutoxycarbonyl; Bn is benzyl, Bz is benzoyl; DIBAL is diisobutylaluminium hydride; Et is ethyl; Ms is mesyl; and, TFA is trifluoroacetic acid.

A compound of the invention wherein L is N can be prepared by reacting a compound of formula CI R 3 R Nd

R

wherein R 2

R

3 R and R 5 are as defined above, with a compound of formula (III): WO 03/042205 PCT/SE02/02055 31

R\

M--

1 11

H

wherein R' is as defined above, in the presence of sodium iodide cand a suitable base (for example a tri(C 1 is alkyl)amine such as triethylamine or Hunig's base), in a suitable solvent (such as a chlorinated solvent, for example dichloromethane) and, for example, at a room temperature (for example 10-30 0

C).

A compound of the invention wherein L is CH can be prepared by reacting a compound of formula (IV):

H

N

R

(IV)

R

14

R

wherein R 2

R

3

R

4 and R 5 are as defined above, with, depending on the compound of the invention it is desired to make: a) an acid of formula R1CO 2 H in the presence of a suitable coupling agent (for example PyBrOP [bromo-tris-pyrrolidino-phosphonium hexafluorophosphate] or HATU) in the presence of a suitable base (such as a tri(CI-6 alkyl)amine, for example diisopropylethylamine) in a suitable solvent (for example N-methylpyrrolidinone or a chlorinated solvent, such as dichloromethane) at room temperature (for example 0

C);

b) an acid chloride of formula R'C(O)Cl or sulphonyl chloride of formula R'S(0) 2 C1, in the presence of a suitable base (such as a tri(C 1 .6 alkyl)amine, for example triethylamine or diisopropylethylamine) in a suitable solvent (for example a chlorinated solvent, such as dichloromethane) at room temperature (for example 0 or, c) an aldehyde of formula R 1 CHO in the presence of NaBH(OAc) 3 (wherein Ac is C(0)CH 3 and acetic acid, in a suitable solvent (such as a C 1 -6 aliphatic alcohol, for example ethanol) at room temperature (for example 10-30°C).

WO 03/042205 PCT/SE02/02055 32 Alternatively, a compound of the invention can be prepared by coupling a compound of formula

M--

L

R

wherein L, M, R 2

R

3 and R 4 are as defined above, with: a) an acid of formula R CO2H in the presence of a suitable coupling agent (for example PyBrOP or HATU) in the presence of a suitable base (such as a tri(C 1 6 alkyl)amine, for example diisopropylethylamine) in a suitable solvent (for example Nmethylpyrrolidinone or a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30 0 or, b) an acid chloride of formula RSC(O)C1, in the presence of a suitable base (such as a tri(Ci-6 alkyl)amine, for example triethylamine or diisopropylethylamine) in a suitable solvent (for example a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30 0

C).

The starting materials for these processes are either commercially available or can be prepared by literature methods, adapting literature methods or by following or adapting Methods herein described.

In a further aspect the invention provides an intermediate of formula In a still further aspect the invention provides processes for preparing the compounds of formula (If) and Many of the intermediates in the processes are novel and these are provided as further features of the invention.

The compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).

The compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of WO 03/042205 PCT/SE02/02055 33 value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS).

According to a further feature of the invention there is provided a compound of the formula (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR5 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof.

The present invention also provides the use of a compound of the formula (Ia), (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvate thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially rheumatoid arthritis). [Respiratory disease is, for example, COPD, asthma (such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) I or rhinitis {acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis and is particularly asthma or rhinitis].

In another aspect the present invention provides the use of a compound of the formula (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).

The invention also provides a compound of the formula (Ie), (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis.

WO 03/042205 PCT/SE02/02055 34 In another aspect the present invention provides the use of a compound of the formula (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in.therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).

The invention further provides the use of a compound of formula (Ic), (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) bronchitis such as eosinophilic bronchitis acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia; (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behqet's disease, Sjogren's syndrome or systemic sclerosis; (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema); (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or WO 03/042205 PCT/SE02/02055 (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man.

The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to still more preferably from 0.10 to 70 and even more preferably from 0.10 to of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible WO 03/042205 PCT/SE02/02055 36 powders, suppositories, ointments, creams, drops and. sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1mg and Ig of active ingredient.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg' 1 to 100mgkg- of the compound, preferably in the range of 0.lmgkg- 1 to 20mgkg' of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The following illustrate representative pharmaceutical dosage forms containing the compound of formula (If) or (Ig) (such as or or a pharmaceutically acceptable salt thereof or a solvent thereof (hereafter Compound for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate WO 03/042205 PCT/SE02/02055 Tablet II mg/tablet Compound X Lactose Ph.Eur. 229 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate (c) Tablet III mg/tablet Compound X Lactose Ph.Eur. 92 Croscarmellose sodium Polyvinylpyrrolidone Magnesium stearate (d) Capsule mg/capsule Compound X Lactose Ph.Eur. 389 Croscarmellose sodium 100 Magnesium stearate Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl 3cyclodextrin may be used to aid formulation.

WO 03/042205 PCT/SE02/02055 38 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise: temperatures are given in degrees Celsius operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0

C;

(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60 0

C;

(iii) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a "Bond Elut" column is referred to, this means a column containing 10g or 20g of silica of 40 micron particle size, the silica being contained in a 60ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, California, USA under the name "Mega Bond Elut SI".

Where an "IsoluteTM SCX column" is referred to, this means a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where "ArgonautT PS-tris-amine scavenger resin" is referred to, this means a tris-(2aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.

(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only; yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vi) when given, 'H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio DMSO (CD 3

SOCD

3 as the solvent unless otherwise stated; coupling constants are given in Hz; (vii) chemical symbols have their usual meanings; SI units and symbols are used; (viii) solvent ratios are given in percentage by volume; WO 03/042205 PCT/SE02/02055 39 (ix) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (APCI) mode using a direct exposure probe; where indicated ionisation was effected by electrospray where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion LCMS characterisation. was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer. The LC comprised water symmetry 4.6x50 column C18 with 5 micron particle size. The eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid. The eluent gradient went from 95% A to 95% B in 6 minutes. Where indicated ionisation was effected by electrospray where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion and (xi) the following abbreviations are used: DMSO dimethyl sulfoxide; DMF N-dimethylformamide; DCM dichloromethane; THF tetrahydrofuran; DIPEA N,N-diisopropylethylamine; NMP N-methylpyrrolidinone; HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',-tetramethyluronium hexafluorophosphate; HBTU O-(7-Benzotriazol-1 -yl)-N,N,N',N-tetramethyluronium hexafluorophosphate; Boc tert-butoxycarbonyl MeOH methanol; EtOH ethanol; and EtOAc ethyl acetate.

WO 03/042205 PCT/SEO2/02055 EXAMPLE 1 This Example illustrates the preparation of N-[1-(3-phenyl-3-[4-methylpiperazin- 1yl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 6 of Table I).

To a solution of 1-methylpiperazine 4 2 pL, 0.38mmol) in DCM (10OmL) was added triethylamine (0.1 mL, 0.72mmol) then N-[1 -(3-phenyl-3-chloropropyl)-piperidin-4-yl]-Nethyl-4-methanesulfonylphenylacetamide (Method A; 180mg, 0.38mmol) and sodium iodide The resulting mixture was stirred at room temperature for 48h then washed with water and brine, dried (MgS04) and evaporated. The residue was purified by eluting through a 20g Bond Elut with 10% methanol in ethyl acetate then methanol then 1% triethylamine in methanol to give the title compound (58mg); NMR: 1.2 1H), 1.3 21H1), 1.4 1H), 1.6 2H), 1.8 411), 1.9 (m,2 2.1 21H), 2.2 3H), 2.4 8H), 2.9 2H), 3.0 (s, 3H), 3.3 2H), 3.8 2H), 7.2 2H), 7.4 2H), 7.9 2H); MS: 541.

The procedure described in Example 1 can be repeated using different secondary amines (such as 4-formylpiperazine, 4-isobutyrylpiperazine or 4-benzylpiperidine) in place of 1 -methylpiperazine.

EXAMPLE 2 This Example illustrates the preparation of N-[1-(3-phenyl-3-[piperidin-4-yl]propyl)piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 17 of Table I).

N-[1-(3-Phenyl-3-[ -tert-butylcarbonyloxypiperidin-4-yl]propyl)-piperidin-4-yl]-Nethyl-4-methanesulfonylphenylacetamnide (Example 3, 4g) was dissolved in trifluoroacetic acid (25mL) and the resulting mixture was stirred at room temperature for 2h. The mixture was evaporated and the residue azeotroped with toluene. The resulting material was stirred with 2M aqueous sodium hydroxide (25mL) and the resulting mixture extracted with DCM (8 x 25mL). The combined extracts were dried and evaporated to give the title compound MS: 526.

WO 03/042205 PCT/SEO2/02055 41 EXAMPLE 3 This Example illustrates the preparation of N-[1-(3-phenyl-3-[l-tert-butylcarbonyloxypiperidin-4-yl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 23 of Table I).

To a solution of 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)propionaldehyde (Method C; 14.4mmol) in DCM (100mL) was added N-(4-piperidinyl)-N-ethyl-4methanesulfonylphenylacetamide (Method B; 4.6g, 14.4mmol) and the resulting mixture was stirred at room temperature for 30min. Sodium triacetoxyborohydride 3 .05g, 14.4mmol) was added and the resulting mixture was stirred at room temperature for 2h. The reaction mixture was washed with 2M aqueous sodium hydroxide (3 x 25mL), dried and eluted through a SCX cartridge with DCM (3 x 25mL), ethyl acetate (4 x 25mL), methanol (4 x 25mL) and finally IM ammonia in methanol (4 x 50mL) to yield crude product which was purified by silica gel chromatography (eluent: ethyl acetate then 10% methanol in ethyl acetate) to yield the title compound 4 MS: 626.

EXAMPLE 4 This Example.illustrates the preparation of N-[1-(3-phenyl-3-[1-methylpiperidin-4yl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 26 of Table I).

To a mixture of N-[1-(3-phenyl-3-[piperidin-4-yl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulfonylphenylacetamide (Example 2, 250mg, 4.76mmol) and formaldehyde (0.2mL, 37% aqueous) in DCM (10mL) was added sodium triacetoxyborohydride (9.52mmol) and the resulting mixture was stirred at room temperature for 18h. The mixture was washed with 2M aqueous sodium hydroxide (10mL) and eluted through a 10g SCX cartridge with DCM (2 x 10mL), methanol (2 x 10mL) and finally IM ammonia in methanol (4 x 10mL) affording the title compound (172mg); MS: 540.

The procedure described in Example 4 can be repeated using different aldehydes (such as acetaldehyde and benzaldehyde) in place of formaldehyde.

WO 03/042205 PCT/SE02/02055 42 EXAMPLE This Example illustrates the preparation of l-(3-phenyl-3-[ 1-acetylpiperidin-4yljpropyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 21 of Table I).

To a mixture of N-Il-(3-phenyl-3- [piperidin-4-yl]propyi)-piperidin-4-yl]-N-ethyl -4methanesulfonylphenylacetamidc (Example 2, 250mg, 4.76mmol) and triethylamine (48mg, 4.76mmol) in DCM was added acetyl chloride (37mg, 4.76mmol). The resulting mixture was stirred at room temperature for 1 8hi, washed with saturated aqueous sodium bicarbonate solution (lOmL), dried and eluted through a lOg SCX cartridge with DCM (2 x l0mL), methanol (4 x lOrrL) and finally 1M ammonia in methanol (4 x lOmL) affording the title compound (180mg); MS: 568.

The procedure described in Example 5 can be repeated using different acid chlorides (such as phenylacetyl chloride and 4-chlorobenzoyl chloride) or sulfonyl chlorides (such as methane sulfonyl chloride) in place of acetyl chloride.

EXAMPLE 6 This Example illustrates the preparation of N-Il-(3-phenyl-3-l -cyclohexylaminocarbonylpiperidin-4-yl]propyl)-piperidin-4-yljJ-N-ethyl-4-me-thanesulfonylphenylacetamide (Compound No. 22 of Table 1).

To a mixture of N-[l1-(3-phenyl-3-[piperidin-4-yl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulfonyiphenylacetamide (Example 2, 250mg, 4.76mmol) and DCM (1lOniL was added cyclohexyl isocyanate (59mg, 4.6mmol) and the resulting mixture was stirred at room temperature for I 8h. The mixture was eluted through a l Og SCX cartridge with DCM (4 x l0mL), methanol (2 x l0mL) and finally 1M ammonia in methanol (4 x IlOamQ affording the title compound (300mg); MS: 651.

EXAMPLE 7 1 -(3-phenyl-3-[4-(2-chlorophenylsulphonyl)piperazin- l-yllpropyl)-piperidin-4-yl]- N-ethyl-4-methanesulphonylphenylacetamide (Compound number 150 of Table 1) 2-Chlorophenylsulphonyl chloride (40.1 mg) was added to a solution of N-[l phenyl-3-[piperazin- 1 -yl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (100 mng) and triethylamnine (53 [t1) in dichloromethane (5 ml) and the mixture was WO 03/042205 PCT/SEO2/02055 43 stirred for 1 hour. The reaction mixture was washed with water, brine and dried.The solvent was removed and the residue was chromatographed on a 10g silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethylacetate) to give the title compound, yield 90mg. MH' 701.

The N-[1-(3-phenyl-3-[piperazin-1-yl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide (Compound 86 of Table 1) used as starting material was prepared following the method described in Example 2 using the appropriate (1-tertbutyloxycarbonyl)-piperazine analogue.

The N-[1 -(3-phenyl-3-[1-tert-butyloxycarbonylpiperazin-1-yl]propyl)-piperidin-4-yl]- N-ethyl-4-methanesulphonylphenylacetamide (Compound 152 of Table 1)used as starting material was prepared following the method described in example 1 using (1-tertbutyloxycarbonyl)piperazine as the amine component EXAMPLE 8 (R or S) N-[1-(3-phenyl-3-[(4- 2,2,2-trifluoroethylsulphonyl-piperazinyl }propyl)piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide. (Compound number 15 of Table 2) Triethylamine (50 p) was added to a solution of (R or S) N-[l-(3-phenyl-3 piperazinyl}propyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide 175 mg) in dichloromethane (5 ml) followed by 2,2,2-trifluoroethanesulphonyl chloride (37 [Il) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with water-and-dried- The residue obtained-on removal -of the-solvent-was- chromatographed-on a 2 0g silica Bond-Elut column eluted with a solvent gradient (ethyl acetate methanol/ethyl acetate) to give the title compound as a white foam, yield 79 mg, MH" 673.

NMR (CDCL 3 1.2 1H), 1.3 2H), 1.4 1H), 1.6-1.8 2.1 2.25 (m, 1H), 2.5 4H), 2.9 2H), 3.0 3H), 3.3 5H), 3.4 1H), 3.6 2H11), 3.8 2H), 7.2 2H), 7.3 3H), 7.4 2H), 7.9 2H).

WO 03/042205 WO 03/42205PCT/SE02/02155 44 EXAMPLE 9 (R or S) l-(3-phenyl-3-(Boc-piperazinyl }propyl)-piperidin-4-yl] -N-ethyl-4methanesuiphonyiphenylacetamiide (R or S) l-(3-pheny[-3-chloropropyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide (594 mg) was added to a solution of triethylamine (0.3 ml) and Boc-piperazine (233 mg) in dichioromethane (10 nil) at room temperature and the mixture was stirred for 14 hours. The reaction mixture was added to a 20g silica Bond-Elut column and was eluted with a solvent gradient (ethyl acetate 40% methanol/ethyl acetate) to give the title compound as a foam, yield 440 mg, MH- 627.

(R or S) N-l1-(3-phenyl-3-chloropropyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide,.

CL O

N/-

0 Methanesuiphonyl chloride (0.5 ml) was added to a stirred mixture of S N-[l phenyl-3-hydroxypropyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (2.7g) and triethylamine (1.64 ml) in dichloromethane (50 ml) at 0 0 C and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was washed with water and dried.

Removal of the solvent gave the title compound as an orange foam, yield 2.4g, MH-' 477.

N-El -(3-phenyl-3-hydroxypropyl)-piperidin-4-yl] -N-ethyl-4methanesuiphonyiphenylacetamide

HO-

0 s=o 0S l-Phenyl-3-(4-toluenesulphonyloxy)propan-1-ol (5g) was added to a mixture of N- (piperidin-4-yl)-N-ethyl-4-methanesulphonylphenylacetamide (5.3g) and potassium carbonate (2.7 1ig) in DMF (100 ml) and the mixture was stirred and heated at 80-90 'C for 6 hours. The reaction mixture was allowed to cool and was evaporated to dryness. The residue obtained WO 03/042205 PCT/SE02/02055 was dissolved in dichloromethane (50 ml) and was washed with water and dried. The solvent was removed and the residue was passed down a 90g silica Bond-Elut column eluted with a Ssolvent gradient ethyl acetate- 20% methanol/ethyl acetate) to give the title compound, yield 2.7g, MH 459. NMR (CDC13) 1.2 1H), 1.3 1.6 2H), 1.75 3H), 1.85 (m, 3H), 2.2 1H), 2.55-2.7 2H), 3.0 3H), 3.1 3.2 2H), 3.3(q, 2H), 3.8(m, 2H), 4.9 1H), 7.3 5H), 7.45 2H), 7.9 2H).

l-Phenyl-3-(4-toluenesulphonyloxy)propan-1-ol is a known compound (CAS No 156453- 52-0) EXAMPLE (R or S) N-[1-(3-phenyl-3 -piperazinyl}propyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide Trifluoroacetic acid 5 ml) was added to a solution of (R or S) N-[1-(3-phenyl-3 Boc-piperazinyl propyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (440 mg) in dichloromethane (10 ml) and the mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was dissolved in 2M aqueous sodium hydroxide and extracted twice with dichloromethane (10 ml each time). The combined extracts were dried and evaporated to give the title compound as a foam, yield 370 mg, MH 527.

EXAMPLE 11 N- [-(3-phenyl-3- 1-(4-chlorobenzoylpiperidin-4-yl)propyl }piperidin-4-yl]-Nethyl-4-methanesulphonylphenylacetamide. (Compound number 26 of Table 2).

To a mixture of N-[1-3-phenyl-3-[piperidin-4-yl]propyl)-piperidin-4-yl]-N-ethyl- 4-methanesulphonylphenylacetamide (330 mg) and MP carbonate resin (670 mg of 2.8 mM/g material) in dichloromethane (10 ml) was added 4-chlorobenzoyl chloride (111 mg) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered and MP 4-toluenesulphonic acid resin Ig) was added to the filtrate and stirred for 30 minutes.

The reaction mixture was filtered and the resin was washed successively with dichloromethane (4X10 ml), 1M MeOH/NH 3 (3X10 ml). The combined washings were evaporated to dryness and the residue was passed through a silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol in ethyl acetate) to give the title compound, yield 121 mg. NMR (DMSOd6): 0.8-2.2 6H) 1.2-1.5 4H) 1.5-2.1 13H) WO 03/042205 PCT/SE02/02055 46 2.4 (in, 1H) 2.7 (in, 3H) 3.3 (in, 4H) 3.8 2H) 7-7.5 (in, .111i) 7.8 2H1). Analytical HPLC on a Chiralcel OJ column (250mm x 4.6 mm) eluted with methanol showed that the chiral purity was >99%.

1- 3 -phenyl- 3 -[piperidin4y]propyl)piperidin4ylpIVethyl-4 miethanesulphonylphenylacetamide. (Compound number 35 of Table 2).

N

N N 0 S=o A solution of N-[l-(3-phenyl-3- tl-(benzyloxycarbonylpiperidin-4yl)propyl }piperidin- 4 -yl]-N-ethyl-4-methanesulphonylphenylacetamide (1 .5g) in ethanol (100 ml) containing 20% Palladium/carbon catalyst (200 mg) was hydrogenated under a hydrogenfilled balloon. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 1.l1g. MS (MHW) 526.

1-(3-phenyl-3- 1 -(benzyloxycarbonylpiperidin-4-yl)propyl Ipiperidin-4-yl]-Nethyl-4-methanesulphonylphenylacetamide. (Compound number 24 of Table 2).

Sodium triacetoxyborohydride (890 mng) was added to a solution of 3-phenyl-3- (benzyloxycarbonylpiperidin-4-yl)propionaldehyde (1 .49g) and N-(4-piperidinyl)-N-ethyl4methanesulphonylphenylacetamide (1 .4g) in dichloroinethane (25 ml) and the mixture was stirred for 1 hour. The reaction mixture was washed with 2M NaOH (2X50 ml) and dried. The solvent was removed and the residue was passed d own a silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate) to give the title compound, yield MS 660.

3 -phenyl- 3 -(benzyloxycarbonylpiperidin-4yl)propioialdehyde Dess-Martin periodinane (1,1,1 -triacetoxy- 1,1 -dihydro- 1,2-benziodoxol-3(l11)-one) (1 .8g) was added to a solution of 3 -phenyl-3-(benzyloxycarbonylpiperidin-4-yl)propano in dichioroinethane (25 ml) and the mixture was stirred for 1 hour, washed with 2M NaOH WO 03/042205 PCT/SE02/02055 47 (2X20 ml) and dried. The dichlorometharie solution containing the title compound was used directly in the next stage.

3 -phenyl- 3 -(benzyloxycarbonylpiperidin-4-yl)propanol Lithium aluminium hydride (9.46 ml of 1M LAH in THF) was added dropwise to a solution of 3 3 -phenyl-3-(benzyloxycarbonylpiperidin-4-yl)propionyl]-(4R,5S)-1,5dimethyl-4-phenyl-2-imidazolidinone Ig) in THF (100 ml) at such a rate that the temperature did not exceed 0°C. The reaction mixture was stirred at -5 0 C for 10 minutes and 2M NaOH was added (10 ml). The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane (20 ml) and dried.

The residue obtained on removal of the solvent was passed through a Bond-Elut column eluted with a solvent gradient (isohexane-60% ethyl acetate/isohexane) to give the title compound, yield 1.6g. MS (MH 354.

3 -phenyl- 3 -(benzyloxycarbonylpiperidin-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4phenyl-2-imidazolidinone.

00 N O N k TMEDA (2.4g) was added to a suspension of cuprous iodide (4.02g) in THF (100 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -78 "C and phenylmagnesium bromide (11.69 ml of a 1M solution in THF) was added and the mixture was stirred at -78 "C for 30 minutes. Dibutylboron triflate (11.69 ml, 1M solution in diethyl ether) was added to a solution of 3-[3-(benzyloxycarbonylpiperidin-4yl)acryloyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone (4.9g) in THF (50 ml) and this mixture was added dropwise over 10 minutes to the solution of the cuprate reagent. The reaction mixture was stirred at -78 "C for 1 hour then allowed to warm to ambient temperature. The solvent was evaporated, the residue was dissolved in ethyl acetate and filtered through silica (100g). The ethyl acetate solution was washed with 2M HC1 (1X100 ml), dried and evaporated to dryness. The residue was passed down a Bond-Elut column WO 03/042205 PCT/SE02/02055 48 eluted with a mixture of ethyl acetate and'isohexane to give the title compound as a single diastereoisomer by NMR. Yield 5.1g. NMR (DMSOd6): 0.5 3H) 0.8-1.1 (m.2H) 1.3 1H) 1.7 2H) 2.6 5H) 2.85-3.1 4H) 5.05 2H) 5.2 1H) 6.8 2H) 7.1- 13H) 3-[3-(benzyloxycarbonylpiperidin-4-yl)acryloyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2imidazolidinone 0*0 l-Chloro-N,N,2-trimethyl-l-propenylamine (1.37g) was added dropwise over minutes to a solution of 3-(benzyloxycarbonylpiperidin-4-yl)propenoic acid (2.5g) in THF ml) and the mixture was stirred for 1.5 hours. Lithium bis(trimethylsilyl)amide (8.65 ml)was added to a solution of (4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone (1.64g) in THF ml) at -10 °C and the mixture was stirred at -10 °C for 10 minutes, allowed to warm to 0 °C and then cooled again to -10 The acid chloride solution (prepared above) was added dropwise and the mixture was allowed to warm to room temperature. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3X50 ml). The combined extracts were dried, evaporated to dryness and the residue was chromatographed on a Bond- Elut column eluted with an ethyl acetate/isohexane mixture to give the title compound, yield 3.6g. NMR (DMSOd6) 0.6 3H) 0.95 1H) 1.2 2H) 1.55 2H) 2.4 1H) 2.3 3H) 2.8 2H) 3.95 3H) 5 2H) 5.3 1H) 6.9 1H) 7.1 2H) 7.2-7.4 (m, 8H).

3-(benzyloxycarbonylpiperidin-4-yl)propenoic acid A mixture of N-benzyloxycarbonyl-4-formylpiperidine (10g), malonic acid pyridine (4 ml) and piperidine (0.4 ml) was heated at 100 oC for 2 hours. The reaction mixture was allowed to cool and was diluted with ethyl acetate (100 ml). The solution was washed with 2M HCI (2X100 ml), dried and evaporated to dryness. The residue was triturated with isohexane to give the title compound, yield 13.5g. NMR (DMSOd6): 1.2 2H) 1.7 2H) WO 03/042205 PCT/SE02/02055 49 2.35 1H) 2.85 2H) 4(d, 2H) 5.05 2H) 5.75 1H) 6.75 1H) 7.35 12.25 (broad peak, 1H) EXAMPLE 12 N-[1-3-[(3-fluorophenyl)-3-[1-phenylpiperidin-4-yl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide. (Compound number 145 of Table 1).

2M NaOH was added to a suspension ofN-[1-[3-(3-fluorophenyl-3-[piperidin-4yl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide di-hydrochloride salt (0.85 g) in dichloromethane (25 ml) and the mixture was stirred until a clear solution was obtained. The dichloromethane solution was dried and filtered. To this dichloromethane solution was added benzeneboronic acid (330 mg), triethylamine (280 mg) and cupric acetate (276 mg). The reaction mixture was stirred for 15 hours, washed with water and filtered through a Chem Elute cartridge. The dichloromethane filtrate was washed with 2M NaOH (3X20 ml), dried and poured on to a 20g SCX cartridge and eluted with methanol (6X20 ml) and 1M ammonia in methanol (6X20 ml). The combined ammonia washings were evaporated and the residue obtained was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate to give the title compound, yield 179 mg.

The N-[1-3(3-fluorophenyl-3-[piperidin-4-yl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide di-hydrochloride salt (Compound number 87 of Table 1) used as starting material was prepared following the procedures of Example 3 and Method C.

EXAMPLE 13 Racemic N-[1-(3-(3-fluorophenyl)-3-[4-(4methanesulphonyl)phenylsulphonyl)piperazin-1 -yl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide (78 mg) (Compound number 59 of Table 1) was separated into its single enantiomers by chromatography on a Gilson preparative HPLC using a 50 mm Chiracel OD column eluted with a mixture of ethanol:isohexane Less polar isomer, yield 2 0mg (Compound number 16 of Table 2) More polar isomer, yield 22 mg (Compound number 17 of Table 2) WO 03/042205 PCT/SEO2/02055 EXAMPLE 14 N1-[1-(3-phenyl)-3- 1-(ethanesulphonylpiperidin-4-yl)propyl}piperidin-4-yl]-N1ethyl-N3-4-methanesulphonylphenylmethyl urea. (Compound number 7 of Table 3).

4-Methanesulphonylphenylmethyl isocyanate 99 mg) in THF (10 ml) was added to 4- N-ethyl- [1-(3-phenyl)-3-{ 1-(ethanesulphonylpiperidin-4-yl)propyl }piperidine(200 mg) and the mixture was allowed to stand at room temperature for 16 hours. The reaction mixture was poured on to a 5g SCX cartridge and was eluted with dichloromethane (3X10 ml), methanol (3X10 ml) and methanolic ammonia (1M, 3X10 ml). The methanolic ammonia washings were evaporated and the residue was dissolved in dichloromethane (20 ml) and isocyanate resin '(200mg) was added. The mixture was stirred for 16 hours, filtered and the filtrate was evaporated to dryness. The residue obtained was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-25% methanol/ethyl acetate) to give the title compound, yield 37 mg. MS (MHR) 633.

4- N-ethyl- [1-(3-phenyl)-3- 1 -(ethanesulphonylpiperidin-4-yl)propyl piperidine o=s

N

ND N A mixture of N-ethyl-N- [1-(3-phenyl)-3- 1-(ethanesulphonylpiperidin-4yl)propyl piperidin-4-yl]-carbamic acid benzyl ester (5g) and 10% Palladium on carbon (2g) in ethanol (200ml) was hydrogenated under a hydrogen filled balloon. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 2.78g.

N-ethyl-N- [1-(3-phenyl)-3- 1-(ethanesulphonylpiperidin-4-yl)propyl piperidin-4-yl]carbamic acid benzyl ester.

WO 03/042205 PCT/SE02/02055 51 Ethanesulphonyl chloride (2.3g) was added to a solution of N-ethyl-N- [l-(3-phenyl)piperidin-4-yl)propyl}piperidin-4-yl]-carbamic acid benzyl ester di-hydrochloride and triethylamine (4.8g) in dichloromethane (200 ml) maintained at 0 The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was washed with 2M NaOH (2X100 ml), dried and evaporated to dryness. The residue was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl methanol/ethyl acetate) to give the title compound, yield 5g. NMR (DMSOd6): 1 3H) 1.1 3H) 1.3-3 14H) 2.2 1H) 2.55-2.9 5H) 2.95 2H) 3.1(q, 2H) 3.4-3.7 3H) 5.05 2H) 7.1-7.4 10H). MS 556.

N-ethyl-N-[l-(3-phenyl)-3- {piperidin-4-yl)propyl piperidin-4-yl]-carbamic acid benzyl ester di-hydrochloride HC1 in dioxan (50 ml of 4M) was added to N-ethyl-N- [1-(3-phenyl)-3-{ 1-tertbutyloxycarbonylpiperidin-4-yl)propyl}piperidin-4-yl]-carbamic acid benzyl ester (26g) at 0 the mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was diluted with diethyl ether (200ml) and the precipitated solid dihydrochloride salt was filtered and dried (hygroscopic). Yield 17g. MS (MH 464.

N-ethyl-N- [1-(3-phenyl)-3- 1-tert-butyloxycarbonylpiperidin-4-yl)propyl}piperidin-4-yl]carbamic acid benzyl ester A solution of 3-phenyl-3-(l-tert-butyloxycarbonylpiperidin-4-yl)propionaldehyde (7.8 g) [prepared following the method described in Example 11] in dichloromethane (200 ml) was added to a mixture of N-ethyl-N-piperidin-4-ylcarbamic acid benzyl ester hydrochloride (7.4g) (CAS No 220395-87-9) and sodium acetate (2.17g) in ethanol (50ml) and stirred for minutes. Sodium triacetoxyborohydride (5.2g) was added in small portions over 15 minutes and stirring was continued for 2 hours. Aqueous NaOH (2M, 200 ml) was added dropwise, the dichloromethane layer was collected and washed with 2M NaOH (2X100 ml), dried and evaporated to dryness to give the title compound, yield 26g. NMR (DMSOd6): 1 3H) 1.35 9H) 1.4-2 14H) 2.3(m, 2H) 2.6-2.7 4H) 3.15 2H) 3.4-4 3H) 5.05 2H) 7.1-7.2 10H). MS (MH 563.

WO 03/042205 PCT/SEO2/02055 52 4-methanesulphonylphenylmethyl isbcyanate Diphenylphosphoryl azide (260 mg) was added to a mixture of 4methanesulphonylphenylacetic acid (200mg) and triethylamine (191 mg) in THF (20 ml) and the reaction mixture was heated under reflux for 4 hours. the reaction mixture was cooled and used directly for the next stage.

Method A N- 1-(3-Phenvl-3-chloroproyl)-piperidin-4-vll-N-ethyl-4-methanesulfonvphenlacetamide Step 1: Preparation of N-[1-(3-phenyl-3-oxopropyl)-piperidin-4-yl] -N-ethyl-4methanesulfonylphenylacetamide To a solution of N-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method B; 3.24g, 10mmol) in DMF (50mL) was added potassium carbonate (2.76g, followed by 3-chloropropiophenone (1.85g, 1 immol). The resulting mixture was stirred at room temperature for 18h then evaporated. The residue was dissolved in DCM and the resulting solution washed with water (4 x 10mL) and brine (10mL), dried (MgSO 4 and evaporated to give the crude product which was purified by eluting through a 50g Bond Elut with 10% methanol in ethyl acetate to afford the sub-titled compound (2.4g, NMR (CDC1 3 1.1 1H), 1.2 2H), 1.6 6H), 2.2 1H), 2.8 2H), 3.0 5H), 3.2 (m, 2H), 3.3 2H), 3.8 2H), 7.4 5H1), 7.9 4H); MS: 457.

Step 2: Preparation of N-[1-(3-phenyl-3-hydroxypropyl)-piperidin-4-yl]-N-ethyl-4methanesulfonylphenylacetamide To a solution of N-[1-(3-phenyl-3-oxopropyl)-piperidin-4-yl]-N-ethyl-4methanesulfonylphenylacetamide (912mg, 2mmol) in ethanol (20mL) at OC was added sodium borohydride (76mg, 2mmol). The resulting mixture was stirred at room temperature for 30min. then evaporated. The residue was dissolved in DCM and the resulting solution washed with water (2 x 5mL) and brine (5mL), dried (MgSO 4 and evaporated to give the subtitled compound (812mg, NMR (CDC1 3 1.1 1H), 1.2 2H), 1.6 8H), 2.0 (m, 2.2 1H) 2.6 2H), 3.0 (s 3.2 2 3.3 (m 21H1), 3.8 2H), 4.9 1H), 7.3 51H1), 7.4 2H), 7.9 2H); MS: 459.

WO 03/042205 PCT/SE02/02055 53 Step 3: Preparation of the title compound To a mixture of N-[1-(3-phenyl-3-hydroxypropyl)-piperidin-4-yl]-N-ethyl-4methanesulfonylphenylacetamide (400mg, 0.87mmol) and triethylamine (0.24mL, 1.04mmol) in DCM (lOmL) at 0°C was added methane sulfonyl chloride (67gL, 0.87mmol). The resulting mixture was stirred at room temperature for 30min. then evaporated. The residue was purified by eluting through a 20g Bond Elut to give the title compound (180mg,.44%); NMR (CDC1 3 1.1 1H), 1.2 2H), 1.6 7H), 2.2 2H), 2.4 2H), 2.8 2H), 3H), 3.3 2H), 3.8 2H), 5.0 1H), 7.3 5H), 7.4 2H), 7.9 2H); MS: 477.

Method B N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenvlacetamide Step 1: Preparation of 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride To a solution of l-phenylmethyl-4-piperidone (25.0g, 132mmol) in THF (250mL) was added ethylamine hydrochloride (12.0g, 147 mol) and methanol (50mL) and the resulting mixture stirred at room temperature for 10min. Sodium triacetoxyborohydride 189mmol) was added portionwise and the resulting mixture stirred at room temperature for lh. 2M Sodium hydroxide solution (250mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K 2 C0 3 and evaporated to give 1phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500mL) and concentrated hydrochloric acid (20mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the sub-titled compound as a solid (38 NMR: (CDC1 3 1.10 3H), 1.40 2H), 1.83 2H), 2.02 2H), 2.65 2H), 2.85 2H), 3.50 2H), 3.75 1H), 7.2 7.4 5H); MS: 219 Step 2: Preparation of N-(1-Phenylmethyl-4-piperidinyl)-N-ethyl-4methanesulfonylphenylacetamide To a solution of 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride (32.0g, 11Ommol) in DCM (500mL) was added N,N-diisopropylethylamine (60mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25.0g, 117mmol), 4dimethylaminopyridine (2.0g) and dicyclohexylcarbodiimide (25.0g, 121mmol) were added and the resulting mixture was stirred at room temperature for 20h. The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous WO 03/042205 PCT/SE02/02055 54 HC1, water and 1N aqueous NaOH, dried (MgSO 4 and evaporated. The residue was purified by silica gel chromatography (eluent: 10% MeOH/ethyl acetate) to afford the sub-titled compound (35 g, NMR: 1.00 and 1.14 3H), 1.45 and 1.70 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 3H), 3.20 and 3.33 2H), 3.45 2H), 3.80 and 3.87 2H), 3.70 and 4.10 1H), 7.2 7.3 5H), 7.48 2H), 7.82 2H); MS: 415 Step 3: Preparation of the title compound To a solution of N-(l-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (34g, 82mmol) in ethanol (600mL) was added ammonium formate (40g). The mixture was purged with argon and 30% Pd on carbon (4.2g) was added. The resulting mixture was stirred at reflux for 4h, then allowed to cool and filtered through diatomaceous earth. The filtrate was evaporated to give a thick oil which solidified on standing to yield the title compound (24.9g, NMR: 1.02 and 1.15 3H), 1.4 -1.6 (br m, 4H), 2.45 2H), 2.93 (br m, 2H), 3.18 3H), 3.20 and 3.32 2H), 3.72 and 4.18 1H), 3.80 and 3.87 (s, 2H), 7.50 2H), 7.85 2H); MS: 325 Method C 3-Phenvl-3-(1-tert-butvlcarbonvloxypiperidin-4-yl)propionaldehvde Step 1: Preparation of 1-tert-butylcarbonyloxy-4-benzoylpiperidine To a solution of 4-benzoylpiperidine (6g, 26.5mmol) in 2M aqueous sodium hydroxide (26.5mL) was added di-tert-butyl dicarbonate (5.79g, 26.5mmol) and the resulting mixture was stirred at room temperature for 18h. The solid product was isolated by filtration and dried under vacuum at 40 0 C giving the sub-titled compound NMR: 1.3-1.4 11H) 1.7 (m, 2H) 2.9 2H) 3.6 1H) 3.95 2H) 7.5-7.6 3H) 7.95 2H).

Step 2: Preparation of ethyl 3-phenyl-3-(1-tert-butylcarbonyloxypiperidin-4-yl)acrylate To a solution of triethylphosphonoacetate (6.2g, 27mmol) in THF (100mL) at 0°C was added lithium bis(trimethylsilyl)amide (32.5mL, 1M, 32.5mmol). The resulting mixture was stirred at 0°C for 20min. 1-tert-Butylcarbonyloxy-4-benzoylpiperidine (7g, 25mmol) was added and the resulting mixture was stirred at room temperature for 48h. The mixture was evaporated and the residue dissolved in ethyl acetate (200mL). The solution was washed with 2M hydrochloric acid (2 x 100mL), dried and evaporated giving the sub-titled compound.

WO 03/042205 PCT/SE02/02055 Step 3: Preparation of ethyl 3-phenyi-3-(1-tert-butylcarbonyloxypiperidin-4-yl)propionoate Ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)acrylate (~25mmol) was dissolved in ethanol (200mL) and the solution purged with argon. 20% Palladium hydroxide (2g) was added and the resulting mixture was stirred at room temperature under an atmosphere of hydrogen (balloon) for 72h. The mixture was purged with argon, filtered and the filtrate evaporated. The crude product was purified by silica gel chromatography (eluent: isohexane then 35% ethyl acetate in isohexane) to give the sub-titled compound (5.3g).

Step 4: Preparation of 3-phenyl-3-(1-tert-butylcarbonyloxypiperidin-4-yl)propan- -ol To a solution of ethyl 3-phenyl-3-(1-tert-butylcarbonyloxypiperidin-4-yl)propionoate (5.3g, 14.6mmol) in THF (100mL) was added lithium aluminium hydride (14.6mL, 1M, 14.6mmol) dropwise over 20min. The resulting mixture was stirred at 0°C for lh. 2M aqueous sodium hydroxide (20mL) was added dropwise. The mixture was filtered through Celite®, washing with ethyl acetate (3 x 25mL). The filtrate and washings were combined and evaporated. The residue was dissolved in ethyl acetate (100mL) and the resulting solution washed with water (3 x 50mL), dried and evaporated to give the sub-titled compound (4.6g); NMR: 0.9-1 2H) 1.25 1H) 1.35 9H) 1.5-2 5H) 2.6 2H) 3.1 2H) 3.8-4 2H) 4.2 1H).

Step 5: Preparation of the title compound To a solution of 3-phenyl-3-(4-1-tert-butylcarbonyloxypiperidin-4-yl)propan- 1 -ol (4.6g, 14.4mmol) in DCM (100mL) was added Dess-Martin periodinane (6.1g, 14.6mmol) and the resulting mixture was stirred at room temperature for 2h. The mixture was washed with 2M aqueous sodium hydroxide (3 x 50mL), dried and evaporated to give the title compound.

WO 03/042205 PCT/SE02/02055 56 Method D N-(tert-butoxycarbonylpiperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide

-<I

0

ONO

0 N H To a solution of 4-methylsulfonylphenylacetic acid (16.1g) in toluene (200ml) under argon was added diphenylphosphoryl azide (16.2ml) and triethylamine (10.4ml). The mixture was heated at 90 oC for 3 hours and then allowed to cool. The tert-butyl- 1-oxo-4-aminoethylpiperidine [CAS 264905-39-7] (17. 10g) in toluene (100ml) was added and the mixture stirred for 18 hours and then partitioned with EtOAc/H 2 0 (500ml/400ml), filtered and the organic layer separated and washed with sat. NaHCO 3 solution. (2 x 300ml), brine (300ml), dried over MgSO 4 filtered and evaporated. The resulting brown oil was purified on silica using a gradient elution of 0 to 3% MeOH in EtOAc to give the title compound as a yellow solid (7.10g); NMR: (DMSO): 1.4 3H), 1.40 9H), 1.52 4H), 2.73 2H), 3.15 4.02 3H), 4.32 2H), 6.89 1H), 7.43 2H), 7.87 2H). MS 340 (MH Boc) N-(piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide 0 NH The piperidine (6.84g) was dissolved in DCM (39ml) and TFA (39m1) was added slowly. The mixture was allowed to stand for 40 minutes and then evaporated. The residue was dissolved in 2M NaOH and extracted with DCM (3x1 50ml) and the extracts dried over MgSO 4 filtered and evaporated to give the title compound as a yellow solid (5.00g); NMR: (DMSO): 1.05 3H), 1.41 4H), 2.42 2H), 2.96 2H), 3.20 5H), 3.90 (quint, 1H), 4.29 2H), 6.84 1H), 7.43 2H), 7.85 2H), MS 340 WO 03/042205 PCT/SE02/02055 57 Method E 1-(3-[3,4-di-fluorophenyl]-3-hydroxypropyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide o 0o F^ fv v

S

F

N

A solution of sodium borohydride (7.7 mg) in ethanol (1 ml) was added to a solution of 1 -(3-[3,4-difluorophenyl] -3-ketopropyl)-piperidin-4-yl]-N-ethyl -4methanesulphonylphenylacetamide (0.25g) in ethanol (3.2 ml) at 0°C under argon and the reaction allowed to warm to room temperature over 20 hours. The reaction was quenched with brine, extracted three times with ether and the combined extracts dried. The filtrate was then concentrated to a clear oil, yield 0.21g. MS (MH 495.

N-[1-(3-[3,4-difluorophenyl]-3-ketopropyl)-piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide: O o F--Q v N"' F N

F

DBU was added to a solution of piperidin-4-yl]-N-ethyl-4methanesulphonylphenylacetamide (CAS number 374725-04-9) (320 mg) and 3,4difluorophenylvinyl ketone (654 mg) in dicholoromethane (9 ml) under argon and the reaction mixture stirred for 36 hours. The reaction mixture was concentrated in vacuo and purified using flash column chromatography on silica eluting with a solvent gradient (methanol 15%, methanol in dicholormethane), yield 250 mg, MH+ 493.

3,4-difluorophenyl vinyl ketone.

Dess martin periodinane (3.18 g) was added to a solution of 3,4-difluorovinyl alcohol (CAS number 149946-84-9) (1.18 g) in dicholoromethane (22 ml) at 0°C under argon and the reaction mixture allowed to stir for 1 hour. The mixture was put directly on to a column for purification via flash column chromatography eluting with a gradient (ethyl acetate WO 03/042205 PCT/SE02/02055 58 ethyl acetate and isohexane) yield 654 mg. NMR (CDC1 3 1H), 6.50 1H), 7.10 (dd, 1H), 7.30 1H), 7.80 2H).

EXAMPLE The ability of compounds to inhibit the binding of RANTES was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with 0. lnM iodinated RANTES, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated RANTES was calculated (IC5o). Preferred compounds of formula have an IC 5 0 of less than EXAMPLE 16 The ability of compounds to inhibit the binding of MIP-la was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with 0.1 nM iodinated MIP-la, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated MIP-la bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated MIP-la was calculated (ICso). Preferred compounds of formula have an IC 5 0 of less than Results from this test for certain compounds of the invention are presented in Table HI.

In Table II the results are presented as Pic50 values. A Pic50 value is the negative log (to base of the IC5o result, so an IC50 of 1pM (that is 1 x 10-6M) gives a Pic50 of 6. If a compound was tested more than once then the data below is an average of the probative tests results.

WO 03/042205 WO 031422Q5PCTSEO2O2O55 Table VIEI, Compound No. Table No Pic5O 4 I 7.84 6 1 6.44 7 1 8.0 9 1 6.51 12 1 6.47 1s 1 8.05 24 1 8.78 27 1 8.9 34 1 7.23 37 1 7.84 Compound No. Table No 42 I 9.2 45 1 8.3 65 1 8.37 69 1 8.85 99 I 8.2 142 I 8.63 15 HI 8.25 18 11 8.46 3 111 8.25 47 INI 8.23 WO 03/042205 WO 03/42205PCT/SE02/02155 PGNa 0 SCHEME 1 PG N aN 14

R

a b or c d or e Conditions a) Reductive amination (R 4

NH

2 NaBH (OAc),) b) Amide formation (R 5 00 2 H, coupling agent or R 5 000I, base) c) Urea formation (isocyanate) d) H 2 Pd (PG is Bn or Bz) e) HOI or TFA (PG is Boo) SCHEME 2 H N 0 14 H N 0 N R 5 14

R

a or b or c N kR 0 NN)KR 14

-R

Cl

R

N 0k Conditions a) Alkyl halide, base b) R 2

C(=O)CH

2

R

3 C HO, AcOH c) R 2

C(=O)CH=CHR

3 d) Reduction then MsCI, base e) Cyclic amine, base, Nal 005053392 61 SCHEME 3 a isl Boc R OEt

R

borc Boc R3

OH

RR

OH

Boc

C

f HN N

R

s

R

I 9 h or I or Conditions a) (EtO),P(-O)CH 2

CO

2 Et, base; (II) hydrogenation Pd(OH) 2

H,)

b) Reduction UAIH) (R 3 is H) c) Reduction to aldehyde DIBAL-H); (II) RSMgBr d) Oxidation Dess-Martin periodlnane) e) MeONHMe, AIMe 3 (li) Reduction (R 3 is H) or R 3 MgBr f) Reductive amlnatlon (NaBH(OAc) 3 AcOH) g) HCI or TFA h) Amide formation (acid coupling reagent or acid halide, base) i) Sulfonamide formation (sulfonyl chloride, base) Reductive amination (aldehyde, NaBH(OAc)) As used herein, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps.

Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.

Claims (16)

1. A compound of formula R1 L0 N N (1) CI wherein L is CHor N; Mis CHor N;provided that Land Mare not both CH; R1 is hydrogen, C,. 6 alkyl. [optionally substituted by phenyl {the phenyl itself optionally substituted by halo, C 14 alkyl, C1 4 alkoxy, cyano, nitro, CF 3 OCF 3 (C14 alkyl)C(O)NH, S(O) 2 NH 2 C 1 4 alkylthio, S(O)(C, 4 alkyl) or S(O) 2 4 alkyl) or heteroaryl. {the heteroaryl itself optionally substituted by halo, C,- 4 alkyl, C,- 4 alkoxy, cyano, nitro, CF 3 4 alkyl)C(O)NH, S(O) 2 NH 2 CI- 4 alkylthio, 4 alkyl) or S(O) 2 (C 1 4 alkyl))}], phenyl f{optionally substituted by halo, C 1 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3 OCF 3 4 alkyl)C(O)NH, S(O) 2 NH 2 C,- 4 alkylthio, S(O)(CI- 4 alkyl) or S(O) 2 (C 1 4 alkyl)}1, heteroaryl {optionally substituted by halo, C 1 4 alkyl, C,1 4 alkoxy, cyano, nitro, CF 3 4 alkyl)C(O)NH, S(O) 2 NH 2 C,- 4 alkylthio, 4 alkyl) or S(O) 2 (C] 4 alkyl)), S(O) 2 R S(O) 2 NR' 0 C(O) 2 6 alkyl), C(0) 2 (phenyl(C,.. 2 alkyl)) or C(O)NHR and when M is CH R' can also be NHS(O) 2 R NHS(O) 2 NHR', NHC(O)R 7 or NHC(O)NHR 7 R 2 is phenyl or heteroaryl, either of which is optionally substituted by halo, C1 4 alkyl, C, 4 alkoxy, S(O)n(C,- 4 alkyl), nitro, cyano or CF 3 R 3 is hydrogen or C 14 alkyl; R 4 is hydrogen, methyl, ethyl, allyl or cyclopropyl; R 5 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C 1 2 )alkyl, heteroaryl (C 1 I 2 )alkyl, phenyl(C 1 2 alkyl)NH or heteroaryl 2 alkyl)NH; wherein the phenyl and heteroaryl rings of R 5 are optionally substituted by halo, cyano, nitro, hydroxy, C 14 alkyl, C1 4 alkoxy, S(O)k(CI4 alkyl), S(O) 2 NR 8 NHS(O) 2 (C, 4 alkyl), NH 2 NH(C1 4 alkyl), N(Cj 4 alkyl) 2 NHC(O)NH 2 C(O)NH 2 C(O)NH(C, 4 alkyl), NHC(O)(C] 4 alkyl), CO 2 H, C0 2 (Ci 4 alkyl), C(O)(C 1 4 alkyl) CF 3 CHF 2 CH 2 F7, CH 2 CF 3 or OCF 3 005053392 63 00 k, mn and n are, independently, 0, 1 or 2; R 6 is C 1 alkyl [optionally substituted by halo, C 1 4 alkoxy,, phenyl {the phenyl itself optionally substituted by halo, C 1 alkyl, C 14 alkoxy, cyano, nitro, CF 3 OCF 3 (C 1 4 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 14 alkyl) or S(O) 2 (C 14 alkyl)) or 5 heteroaryl. {the heteroaryl. itself optionally substituted by halo, C 14 alkyl, C 14 alkoxy, cyano, nitro, CF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2 (C 14 alkyl))], C 3 7 cycloalkyl, pyranyl, phenyl {optionally substituted by halo, c-i C 14 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3 OCF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2 (C 1 4 alkyl)) or heteroaryl {optionally substituted by halo, C 14 alkyl, C 14 alkoxy, cyano, nitro, CF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 14 alkyl) or S(O) 2 (CI 4 alkyl)); R 7 is hydrogen, C 1 alkyl [optionally substituted by halo, C 14 alkoxy, phenyl, {the phenyl itself optionally substituted by halo, C 14 alkyl, C 14 alkoxy, cyano, nitro, CF 3 OCF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 14 alkyl) or S(O) 2 (C 1 4 alkyl)) or heteroaryl {the heteroaryl itself optionally substituted by halo, CI- 4 alkyl, C 1 4 alkoxy, cyano, nitro, CF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 1 4 alkyl) or S(O) 2 (C 1 4 alkyl)} C 3 7 cycloalkyl, pyranyl, phenyl, {optionally substituted by halo, C 1 4 alkyl, C 14 alkoxy, cyano, nitro, CF 3 OCF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C 14 alkyl) or S(O) 2 (C 14 alkyl or heteroaryl {optionally substituted by halo, C 14 alkyl, C 14 alkoxy, cyano, nitro, CF 3 (C 14 alkyl)C(O)NH, S(O) 2 NH 2 C 14 alkylthio, S(O)(C, 4 alkyl) or S(O) 2 (Cl 4 alkyl); R 8 and R 9 are, independently, hydrogen or C 14 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C 14 alkyl, C(O)H or C(O)(C 14 alkyl); R and R are, independently, hydrogen or C 14 alkyl, or may join to form a 5- or 6- membered ring which is optionally substituted with C 1 4 alkyl, or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C 1 4 alkyl, C 14 alkoxy, S(O)m..C1 4 alkyl, S(O) 2 NH 2 S(O) 2 NH(CI 4 alkyl), S(O) 2 NH(CI 4 alkyl) 2 NHS(O) 2 4 alkyl), NH 2 NH(C 14 alkyl), N(C 14 alkyl) 2 NHC(O)NH 2 C(O)NH 2 C(O)NH(C 1 4 alkyl), NHC(O)(C 1 4 alkyl), CO 2 H, C0 2 (C 1 4 alkyl), C(O)(C 14 allkyl), CF 3 CHF 2 CH 2 F, CH 2 CF 3 or OCF 3 or a pharmaceutically acceptable salt thereof or a solvate thereof;, WO 03/042205 PCT/SE02/02055 64 provided that when R' is hydrogen or unsubstituted alkyl, R 4is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl'or heteroaryl part of R 5 is substituted by One Of: S(O)kCl. 4 alkyl, NHC(O)NH 2 C(O)(C 1 4 alkyl), CHF 2 CH 2 F, CH 2 CF 3 or OCF 3 and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C 1 4 alkyl, CI- 4 alkoxy, S(O)kCl. 4 alkyl, S(0) 2 NR 8 R 9 NHS(O) 2 (C 1 4 alkyl), NH 2 NH(Ci- 4 alkyl), N(CI- 4 allcyl) 2 NHC(O)NH 2 C(O)NH 2 C(O)NH(C- 1 4 alkyl), NHC(O)(C 1 4 alkyl), CO 2 H, C0 2 (C 1 4 alkyl), C(O)(CI- 4 alkyl), CF 3 CHF 2 CH 2 F, CH 2 CF 3 or OCF 3

2. A compound as claimed in claim 1 wherein L is CHi.

3. A compound as claimed in claim I or 2 wherein M is N.

4. A compound as claimed in claim 1, 2 or 3 wherein R 1 is phenyl (optionally substituted by halo, C 14 alkyl, C 1 4 alkoxy, CF 3 or OCF 3 S(O)2(Cp-4 alkyl), S(O) 2 (Cl. 4 fluoroalkyl), S(O) 2 phenyl (optionally substituted by halo, cyano, C 1 4 alkyl, CI. 4 alkoxy, CF 3 OCF 3 S(O) 2 (CI- 4 alkyl) Or S(O) 2 (C 1 4 fluoroalkyl)), benzyl (optionally substituted by halo, C 1 4 alkyl, Cb-4 alkoxy, CF 3 or OCFA) benzoyl (optionally substituted by halo, C 1 4 alkyl C1- 4 alkoxy, CF 3 or OCFA) C(O)NHphenyl (optionally substituted by halo, C 14 alkyl, C 1 4 alkoxy, CF 3 or OCF 3 S(O) 2 thiophenyl, CH 2 pyridinyl, CH 2 quinolinyl or CH 2 thiazolyl.

A compound as claimed in claim 1, 2, 3 or 4 wherein R 2 is phenyl optionally substituted by halo.

6. A compound as claimed in claim 1, 2, 3, 4 or 5 wherein R 3 is hydrogen or methyl.

7. A compound as claimed in claim 1, 2,3, 4,5 or 6 wherein R 4 is ethyl.

8. A compound as claimed in claim 1, 2, 3, 4, 5, 6 or 7 wherein R 5 is phenyl(CI- 2 )alkyl, phenyl(C 1 2 alkyl)NH, phenyl, heteroaryl or heteroaryl(Cl-z)alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyarlo, nitro, hydroxy, C 1 4 alkyl, C 1 4 alkoxy, S(O)kCI- 4 alkyl, S(O) 2 NR R 9 NHS(O) 2 (C 1 4 alkyl), NH 2 NH(CI. 4 005053392 00 0 alkyl), N(CA4 alkyl) 2 NHC(O)NH 2 C(O)NH 2 C(O)NH(Ci4 alkyl), NHC(O)(ClA G alkyl), CO 2 H, CO 2 (C 4 alkyl), C(O)(C 14 alkyl), CF 3 CHF 2 CH 2 F, CH 2 CF 3 or OCF 3 Cc and R 8 and R 9 are, independently, hydrogen or ClA alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C 4 alkyl, C(O)H or C(O)(C- 4 alkyl); and k is 0,1 or 2.

9. A process for preparing of a compound as claimed in any one of claims 1 to 8 C comprising: O i where L is N, reacting a compound formula (II): SC R 3 R2N 0 (II) L N R 4 with a compound of formula (III): M-- R' o I -NH in the presence of sodium iodide and suitable base, in a suitable solvent; where L is CH, reacting a compound of formula (IV): HN R 3 (IV) N 0 R2N R R 4 with: an acid formula R'CO 2 H in the presence of suitable coupling agent in the presence of a suitable base in a suitable solvent; an acid chloride of formula R'C(0)C1 or sulphonyl chloride of formula R'S(O) 2 C1, in the presence of a suitable base in a suitable solvent; or, 005053392 66 00 O an aldehyde of formula R'CHO in the presence of NaBH(OAc) 3 (wherein Ac is C(O)CH 3 and acetic acid, in a suitable solvent; iii. coupling a compound of formula R1 M (V) L H n N N SR 4 R2 with: an acid of formula RSCO 2 H in the presence of a suitable coupling agent in the presence of a suitable base in a suitable solvent; or an acid chloride of formula RC(O)C 1, in the presence of a suitable base in a suitable solvent.

10. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof or solvate thereof, for use as a medicament.

12. A compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof or solvate thereof, in the manufacture of a medicament for use in therapy.

13. A method of treating a CCR5 mediated disease state comprising administering to a patient in need of such treatment an effective amount of a compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof or solvate thereof.

14. An intermediate of formula 005053392 67 00 O CO R 1 M (V) R4 N N ND wherein L, M, R 1 R 2 R 3 and R 4 are as defined in claim 1.

15. A compound according to claim 1, substantially as hereinbefore described O 0herein with reference to any one of the examples.

16. A process according to claim 9, substantially as hereinbefore described with reference to any one of the examples.